RAT STRAINS
There are three main classes of rats used in research; these include inbred strains, outbred stocks, and mutants (including transgenic stocks). It is very important that research workers understand the characteristics of these three classes of stock, as the understanding may have a profound influence on the quality of their research. For example, outbred stocks such as Wistar rats may be segregating at many genetic loci that are important in drug metabolism, so that different individuals within a colony will react differently. In many cases it does not make much sense to do detailed pharmacological studies against such a variable genetic background. The characteristics of the three main classes of stock are briefly summarized next.
Inbred strains
Inbred strains are produced by at least 20 generations of brother x sister mating, with all
individuals being derived from a single breeding pair in the 20th or subsequent
generation (this eliminates parallel sublines). For most practical purposes, an inbred strain can
be regarded as an immortal clone of genetically identical individuals. Inbred strains are named
according to rules formulated by the ICLAS Committee on Rat Nomenclature. The most recent rules can
be found in Gill et al. (1992). Very briefly, they are designated by a code consisting of an upper
case letter or letters in Roman type (e. g. ACI, LEW, SHR). Symbols including numbers are allowed
for strains already well known by a designation including numbers (e. g. F344). No further name is
required. It is not necessary or desirable to write, for example, about the “Fischer
F344” rat strain. When an inbred strain has been separated into a number of branches for a
number of years, particularly if the separation occurred in the early years of inbreeding, then
genetic differences among the branches or “substrains” are likely to occur as a result
of new mutations or residual genetic variation that was not eliminated at the time the colonies
were separated. Substrains of this type are indicated by a slash and some letters or numbers to
identify the substrain (e. g. F344/N is the substrain maintained by the National Institutes of
Health, designated by “N”).
Inbred strains have a number of properties that make them the animal of first choice
for most types of research. As the strain is isogenic (i. e. all individuals are genetically
virtually identical), the genotype of the whole colony can be determined at a particular genetic
locus by typing a single individual. Many genetic markers are fixed in each strain so that the
authenticity of the strain can be determined. This can now be done using DNA markers detected
using the polymerase chain reaction (Lewis et al., 1994). This contrasts sharply with outbred
rats, where currently there are not even any genetic markers that can be used to distinguish
between Wistar and Sprague-Dawley stocks.
All inbred animals are homozygous at all genetic loci, so there are no
“hidden” recessive genes that could cause confusion in experiments involving breeding.
As a result of this homozygosity, the strain stays genetically constant for many generations. This
is valuable, as it makes it possible to build up background data on genetic characteristics that
should remain valid for a long period of time. Of course, the phenotype (but not the genotype) may
alter if the diet, environment, or associated microorganisms change. But over a period of several
generations, an inbred strain will remain much more constant than an outbred stock.
The isogenicity and homozygosity together tend to lead to greater phenotypic
uniformity of inbred animals. This is important, as greater uniformity leads to more statistically
powerful experiments, which are able to detect a given biological effect with fewer animals. The
degree of the contrast with outbred stocks depends on the character being studied. Clearly, for
characters controlled by a single or small numbers of genetic loci such as the major
histocompatibility complex or the drug-metabolizing enzymes, animals within an inbred strain will
be uniform whereas animals of an outbred stock will usually not be so. However, the greater
uniformity of inbred animals may not be apparent for characters such as body and organ weights
(which also depend on environmental and chance factors), unless very large numbers are studied.
Each inbred strain has its own unique pattern of behavior, growth patterns, reproductive
performance, spontaneous disease (including tumors), and response to xenobiotics. Differences
among strains are, of course, an indication that the observed character is under genetic control.
However, it is important to avoid the use of a strain if it is inappropriate for a particular
project. For example, strain SHR develops hypertension, and is widely used for cardiovascular
research, bot it would probably be inappropriate to use it for carcinogenesis screening. Currently,
there are over 200 inbred rat strains. A list of about 140 these (the number known at that time)
together with brief details of their characteristics is given by Greenhouse et al. (1990).
Outbred Stocks
So-called “outbred stocks” are usually maintained as closed colonies of rats of
undefined genotype and sometimes known by generic names such as Wistar, Sprague-Dawley, or
Long-Evans, which indicate their historical origin. They may also be known by a code designation
given by the breeder, which helps to distinguish one colony of Wistar rats from another (for
reasons noted later, any two colonies of Wistar rat are likely to be genetically different).
Nomenclature rules were formulated by Festing et al. (1972), though they have not been widely adopted.
The amount of genetic variation present in any
given colony depends on its history. At one extreme, if the colony has been maintained as a closed
colony for many years with small numbers of breeding animals each generation, it may be genetically
highly uniform to the extent that it will closely approximate an inbred strain. If the colony has
become inbred, it may have gone through a period of rapid genetic drift so that it will differ from
other colonies with the same historical origin. At the other extreme, a colony that has recently
been crossed to an unrelated stock should be genetically highly variable.
Outbred stocks have one advantage over inbred
strains: The animals are less expensive. However, users should be aware that the use of less
expensive animals might result in relatively poor quality, and possibly expensive, research.
Outbred stocks may “drift” dramatically in their characteristics over a short period of
time. For example, the life span of the Charles River Sprague-Dawley male rats declined
dramatically from about 70% to about 40% survival at 24 mo of age in 1988 with the introduction of viral-antibody-free rats, with the suspicion that much of the change was due to a genetic change in
the stock (Nohynek et al., 1993). However, Rao et al. (1990) also found a decline in the 106-wk
survival of F344 male rats from about 81% to 68% over an 11-yr period, which suggests that
environmental factors may also have reduced survival, as F344 rats should have stayed genetically
almost constant during this period. Such unexpected changes can be expensive. Individual samples of
rats from an outbred colony may differ markedly in their genetic characteristics (Takahara et al.,
1994), making it difficult to study xenobiotic metabolism. Where there is substantial genetic
variability, the increased phenotypic variation implies that larger sample sizes are necessary to
provide reasonable statistical precision. The claim that is sometimes made that humans are not
isogenic and hence isogenic animals should not be used as models for humans is based on false
logic. One of the advantages of using rats for research is that isogenic strains are available and
offer a much more powerful research tool than non-isogenic stocks. In fact, isogenic humans are
available on a limited scale in the form of monozygous twins. These would be ideal for clinical
trials, but their use is severely limited by their rarity.
Mutants and transgenics
Over 300 genetic loci associated with mutants and polymorphisms of various sorts have been described in the rat (Hedrich, 1990). Some of these, such as the polymorphisms associated with drug-metabolizing enzymes, and mutants such as acholuric jaundice (widely known as the Gunn rat) and the Rowett athymic nude, are important in pharmacological and toxicological research. More recently, “mutants” such as the Big Blue rats have been produced using transgenic techniques. Transgenic and “knockout” rats produced by gene-targeting techniques are likely to be of increasing importance in toxicological research. Mutants and transgenes can be placed on any genetic background by suitable breeding techniques. Thus, the jaundice gene from the Gunn rat is available on the inbred ACI, LEW, R/A, and RHA genetic background, as well as on a number of outbred genetic backgrounds. For this reason, it would be incorrect to discuss drug metabolism in “the Gunn rat” (or any other mutant or transgenic) without specifying its genetic background because drug metabolism will depend on many genes in addition to the specific locus that is abnormal in the Gunn rat.
Choice of strain in research and screening
There seem to be no serious disadvantages (apart from cost), and many advantages, in the use of inbred strains rather than outbred stocks in academic research (Festing, 1979). These animals offer the nearest equivalent to pure reagents that is possible when using animals in research, particularly if they are also of a high health status. In disciplines other than toxicology there has been a relentless trend toward the increased use of inbred strains. It is not entirely clear why their use is not more widespread in toxicological research. Any disadvantage in terms of initial cost should be amply compensated for by improved research quality and the need for fewer animals. In toxicological screening the relative merits of inbred strains versus outbred stocks have been debated for over 50 yr without reaching a consensus (Goodman et al., 1994). An inbred rat strain F344 is used in the National Toxicology Program Carcinogenesis Bioassay (NTP-CB), but most commercial screening is done using outbred stocks (McAuslane et al., 1991). Festing (1993, 1995) has argued in detail the case for using more than one isogenic strain in carcinogenesis s creening, but without increasing the total number of animals used. In the rest of this review outbred stocks are referred to by spelling the name in full (e. g. Wistar, Sprague-Dawley, Long-Evans) and inbred strains are designated by their official code (e. g. F344, LEW, COP, WKY, etc.). For the sake of brevity, the word “strain” is sometimes used to mean “strain or stock”. In the sections that follow, species differences on target organs are reviewed including the effects on liver, kidney, lung, mammary gland, urinary bladder, duodenum, pancreas, pituitary gland, and nervous system. While comparisons of susceptibility to carcinogenesis among strains are described for certain tissues, the focus of this review is on agents for which few carcinogenic data are available.
LIVER
The metabolism of normal cellular constituents, including fat, differs in the liver between strains. For example, Goodman et al. (1994) noted that Sprague-Dawley rats became obese (24% mean body fat) upon aging to 24 months while F344 rats usually remain lean (15% mean body fat). De Antueno et al. (1994) found that hepatic delta fatty acid desaturases required converting linoleic acid to metabolites were only 50% as active in Sprague-Dawley than in Wistar or Long-Evans rats. This would account for the observed differences in weight between these stocks. Of more importance is the implication of fatty acid metabolism in disease processes and the need to use more than one rat strain in interpretation of data for humans (de Antueno et al., 1994). There may also be marked differences in body weight responsiveness to chemicals. Although a pharmaceutical agent was not examined, the anorexia produced by fenfluramine resembles weight loss induced by 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD) (Unkila et al., 1994). TCDD induced a decrease in body weight and plasma β-endorphin as well as an increase in brain serotonin metabolism and plasma free tryptophan in Long-Evans rats without an effect in Hanover Wistar rats (Unkila et al., 1994; Pohjanvirta et al., 1993). Since the responsiveness of rat strains to anorexic compounds differs, drug development to counteract obesity may lack success if a resistant strain is selected for study.
Cytochrome P-450 Isozymes
The most important enzymic system involved in biotransformation is the hepatic microsomal cytochrome P-450 system (Sipes and Gandolfi, 1986). In an extensive review on hepatic microsomal enzymes, Conney (1967) suggested that there were strain differences in the liver mixed-function microsomal oxidase activities and the ability to induce this enzymic system. This may account for the observed differences in responsiveness to xenobiotics. A summary of numerous studies comparing total cytochrome P-450 content and isozyme levels among various strains is given in Table 1. There is a general consensus that the actual total microsomal enzyme content does not vary widely among strain but that determination of isozyme responsiveness is a more relevant biological determinant of strain differences. The study by Koster et al. (1989) points out the importance of rat purchase source as a factor in strain variability in isozyme responsiveness within a strain. The rats utilized in these studies came from four different European suppliers, so differences in diet, husbandry, and microflora could have contributed to the apparent strain variability.
Table 1. Summary of Hepatic Cytochrome P-450 Content Studies with Various Strains
|
Strain/stock |
Results |
References |
|
Sprague-Dawley, |
Total cytochrome |
Page and Vesell (1969); Creel et al. (1976); |
|
Sprague-Dawley, |
Variation in total |
Kai et al. (1988); Augustine and Zematis (1989); |
The phenobarbital induction of the microsomal
mixed-function oxidase system is a complex phenomenon. In studies where investigators used more
than one strain, there was a marked difference in responsiveness of hepatic microsomal isozymes to
phenobarbital induction
(Table 2).
For example, phenobarbital induced a sixfold higher
increase in testosterone hydroxylase activity in Wistar than in Sprague-Dawley rats (Shefer et al.,
1972). In another case, phenobarbital was found to induce hepatic epoxide hydrolase equally in ACI
and F344 rats but it only increased cytosolic aldehyde dehydrogenase (ALDH) in the ACI strain
(Jones and Lubet, 1992), indicating a difference in sensitivity with respect to a specific isozyme.
With the development of more sophisticated
technology and a greater understanding of the microsomal cytochrome P-450 system, numerous studies
have shown strain-related differences in hepatic enzyme induction. By means of spectral analysis,
immunological reactivity, polyacrylamide gel electrophoresis, peptide analysis, immunoprecipitin
analysis, peptide mapping, and catalytic activities toward substrates such as aminopyrine, aniline,
benzo[a]pyrene, ethylmorphine, etc., eight different forms of cytochrome P-450 were identified in
rat liver microsomes (Guengerich et al., 1982). In a series of experiments (Guengerich et al.,
1981, 1982; Larrey et al., 1984), polymorphic differences in the responsiveness of the various
hepatic microsomal P-450 isozymes to inducing agents such as phenobarbital and 3-methylcholanthrene
were found within one outbred stock (Table 2).
As noted in the discussion of the properties of outbred stocks, the extent of polymorphisms of this
type will depend on the previous history of the individual colony.
Table 2. Summary of Phenobarbital Induction Studies on Hepatic Cytochrome P-450 Isozymes
|
Strain/stock |
Agent |
Results |
References |
|
Sprague-Dawley, Phenobarbital |
Phenobarbital |
Total P-450 content and isozyme induction similar in strains |
Page and Vesell (1969); |
|
Wistar, Gunn, |
Phenobarbital |
Differences in cytochrome P-450 isozyme induction among strains |
Celier and Cresteil (1989); |
|
Sprague-Dawley, |
Phenobarbital, |
Differences in cytochrome |
Bandiera et al. (1986); |
Recently, Kitareenwan and Walz (1994) reported
marked differences of cytochrome P-450 isozyme expression among four inbred strains of rat.
Metabolism of progesterone via the CYP2C11
microsomal component was highest in strain SHR, followed by F344, and in both it was greater than
in WKY. In contrast, warfarin metabolism via the CYP2A1 component was highest in WKY and least in
SHR rats. The relevance of this finding is not merely a notation of a difference between rat
strains but also of the fact that WKY are utilized as “normotensive controls” for the hypertensive
strain SHR (Kitareenwan and Walz, 1994). There is no apparent evidence that the cytochrome P-450
system is in any way associated with the regulation of blood pressure. If SHR and WKY differ at
many loci not associated with blood pressure, the use of WKY as a normotensive control strain for
SHR is questionable, as noted previously by other authors (Rapp, 1987; Festing and Bender, 1984).
In addition to enzymic detoxification it has
been found that hepatocytes express a transporter P-glycoprotein, which is a plasma membrane
transporter involved in the excretion of drugs from liver cells through a pumping mechanism into
the biliary canaliculus (Kamimoto et al., 1989). In a recent study, Chieli et al. (1994)
demonstrated that dexamethasone suppressed P-glycoprotein expression in F344 rat hepatocytes to a
greater extent than in Sprague-Dawley and Wistar rats. These findings indicated that F344 rats
displayed a decreased ability to extrude chemicals and may be more prone to toxicity.
Peroxisomal Proliferation
The hypolipidemic agents were developed to lower serum cholesterol and triglycerides. However, chronic administration of this class of drugs resulted in hepatic enlargement and proliferation of peroxisomes (Orton et al., 1984). Ingestion of clofibrate for 10 d produced a similar increase in liver weight, cytochrome P-450 content, and peroxisomal proliferation in Wistar and Sprague-Dawley rats (Lundgren and DePierre, 1989). Despite these similarities, clofibrate elevated microsomal epoxide hydrolase activity accompanied by a decrease in glutathione transverse activity only in the Sprague-Dawley strain. Similarly, Pill et al. (1992) found that LEW rats were far more susceptible to peroxisomal proliferation than Sprague-Dawley animals, as evidenced by the marked rise in hepatic total peroxisomal oxidation activities and cytochrome c oxidase activity in LEW rats. In a comparison of various strains Makowska et al. (1990) demonstrated that ciprofibrate induced a ninefold increase in peroxisomal fatty acid-oxidase in Sprague-Dawley, Wistar, and F344 strains, whereas a marked 35-fold elevation was noted in Long-Evans rats. Measurement of catalase, a peroxisomal enzyme marker, revealed a significant increase in Sprague-Dawley and Wistar rats but a decrease in F344 animals. In a recent study Biegel et al. (1992) demonstrated that the basal levels of hepatic b-oxidation activity, a metabolic marker of peroxisome proliferation, and hepatic cell replication (cell number) were approximately twofold higher in Sprague-Dawley rats compared to F344 animals. Treatment with the anti-hypercholesterolemic drug WY-14,643 at 50 or 1000 ppm produced a maximal peroxisomal proliferation in Sprague-Dawley rats to 3.7-fold above control. However, in F344 rats administration of 1000 ppm WY-14,643 induced a 5.4-fold increase above control in hepatic peroxisomal proliferation. It is evident that strain-related differences exist with respect to drug-induced hepatic peroxisomal proliferation and that the factors involved are complex, which makes it especially difficult to extrapolate to humans for liver toxicity and carcinoma.
Mycotoxins
Differences in the hepatocarcinogenic potential of mycotoxins between rat strains are thought to be associated with variation in metabolic capacity. DA strain rats are poor metabolizers for the gene CYP2D6 regulating debrisoquine-4-hydroxylation, whereas LEW and F344 rats are extensive metabolizers. It has been suggested that there is an association between susceptibility to carcinoma development and the common human autosomal recessive debrisoquin-sparteine polymorphism (Hirvonen et al., 1993; Agundez et al., 1994). This polymorphism alters CYP2D6 and results in two phenotypes where homozygosity for mutant alleles such as CYP2D6 (C) results in a poor metabolizer. Hietanen et al. (1986) found that DA rats were more resistant to cancer induction and hepatic toxicity by ochratoxin A than LEW rats, suggesting the possibility that the presence of CYP2D6 mutant alleles provides protection against ochratoxin-induced tumorigenesis, though DA and LEW rats differ at many other loci. However, in LEW rats CYP2D6 does not undergo mutation to the mutant allele form such that there was a threefold higher ochratoxin 4-hydroxylase activity. In addition, the DA rat liver S9 fraction possessed a two- to fourfold diminished capacity to activate aflatoxin into bacterial mutagens. The enhanced ochratoxin 4-hydroxylase activity and S9mediated mutagenicity would account for the observed multiple hepatomas seen in LEW rats. Boorman et al. (1992) found that F344 rats were susceptible to ochratoxin-induced renal lesions; however, the female appeared more resistant, a phenomenon seen with numerous chemicals. Although the strain-related differences in susceptibility to mycotoxin-induced tissue damage may be due to metabolic differences, the role hormones play seems to be critical in the outcome (Clemens et al., 1979). Similarly, Plummer et al. (1987) found that F344 rats produced a twofold increase in adducts of aflatoxin B with DNA compared to DA animals, and this was accompanied by hepatocarcinogenicity in the F344 strain. In general, the DA strain appeared resistant to mycotoxin-induced hepatotoxicity (Table 3).
Table 3. Differential strain sensitivity to naturally occurring substances
|
|
|
Strain/stock |
|
|
|
Substance |
Effect |
Resistant a |
Susceptible |
Reference |
|
Ochratoxin A |
Hepatotoxicity |
DA |
LEW |
Hietanen et al. (1986) |
|
|
Renal lesions |
– |
F344 |
Boorman et al. (1992) |
|
Aflatoxin B |
Hepatocarcinoma |
DA |
F344 |
Plummer et al. (1987) |
|
Monocrotaline |
Pulmonary hypertension |
F344 |
Sprague-Dawley |
Pan et al. (1993) |
|
Bracken fern |
Urinary bladder tumors |
Sprague-Dawley |
F344 |
Pamukcu et al. (1980) |
|
Betel nut quid |
Pancreatic tumor |
Sprague-Dawley |
F344 |
Hoffmann et al. (1994) |
|
Bracken Fern |
Intestinal tumors |
Sprague-Dawley |
F344 |
Pamukcu et al. (1980) |
|
Hydrazines |
Colonic carcinoma |
WF |
Long-Evans |
Takizawa et al. (1978) |
a
Resistant does not imply an absolute lack of response but a significantly lower incidence than in susceptible.KIDNEY
Drug-induced injury associated with metabolic activation processes is not unique to the
liver. In addition to carrying out the primary function of chemical elimination via excretion, the
kidney serves as a site for metabolic activation and/or detoxification of drugs. There is a marked
difference in the ability to catalyze the sulfate conjugation step of phenolic drugs and phenolic
monoamines (phenol sulfotransferase) in kidney of various rat strains. Maus et al. (1982)
demonstrated that induction of renal phenol sulfotransferase with dexamethasone produced a slight
23% increase in activity in F344 rats but a marked 317% rise in Sprague-Dawley animals. As does
the liver, the kidney contains microsomal oxidase enzymes (Mitchell et al., 1977). A number of
hydrocarbons including decalin and d-limonene cause the accumulation of hyalin droplets in
the kidney, and with chronic administration result in a significant incidence of kidney tumors in
male but not in female F344, Sprague-Dawley, BUF, or BN rats. Ridder et al. (1990) showed that
susceptibility is associated with the accumulation of a 2u-globulin, which
is a urinary protein produced by male but not female rats. NBR is the only known rat strain in
which males do not produce significant amounts of a 2u-globulin, and this strain is not
susceptible to the development of these kidney tumors. This is an important example of a study
where an understanding of mechanisms based on genetic (strain and sex) factors substantially
increases the confidence with which human risk may be assessed. Humans do not produce urinary
proteins that are identical to a 2u-globulin so will not be
expected to develop kidney tumors, at least by this mechanism, when exposed to these hydrocarbons.
Elevated total cytochrome P-450 has been
associated with acetaminophen-induced nephrotoxicity either by direct activation or through
deacetylation of acetaminophen to the toxic metabolite p-aminophenol in F344 but not
Sprague-Dawley rats (McMurtry et al., 1978). However, Newton et al. (1983a, 1983b) demonstrated
that the differences between F344 and Sprague-Dawley rats in responsiveness to acetaminophen-induced
nephrotoxicity were not due to differences in total renal cytochrome P-450 content. They suggested
that the enhanced susceptibility of F344 rats to acetaminophen-induced nephrotoxicity may be due
to activation of a specific cytochrome P-450 isozyme that is either absent or less responsive in
Sprague-Dawley rats (Newton et al., 1983b).
One of the factors to consider in drug-induced
differences in renal responsiveness of rat strains is the ability of chemicals to reach the kidney,
which may account for the reported diversity of adverse reactions. In a study with acetaminophen,
young (2-3 mo old) F344 rats exhibited a decreased urinary excretion of parent compound and the
metabolite p-aminophenol accompanied by renal dysfunction (increased BUN) and histopathologic
damage (Tarloff et al., 1989). In contrast, Sprague-Dawley rats appeared resistant to
acetaminophen-induced nephrotoxicity at this age. Tarloff et al. (1989) suggested that
acetaminophen pharmacokinetics (plasma half-life, volume of distribution, and rate of total
clearance) may account for differences in nephrotoxicity between F344 and Sprague-Dawley rats.
Support for this hypothesis is gained from the finding that Sprague-Dawley rats excrete higher
concentrations of urinary tobramycin over a 24-h period compared to F344 rats (Reinhard et al.,
1994). The decreased ability to excrete tobramycin may be related to enhanced nephrptoxicity in
F344 rats. Reinhard et al. (1991) found that F344 rats were more susceptible to the nephrotoxic
actions of the aminoglycoside tobramycin, as evidenced by histopathologic score, compared to
Sprague-Dawley animals. In a recent study Goodrich and Hottendorf (1995) found that a 90-mg/kg dose
of tobramycin failed to markedly alter renal function in Sprague-Dawley rats, but a 30-mg/kg dose
of antibiotic significantly decreased serum creatinine and BUN and produced histopathologic
alterations in kidneys of F344 rats. It should be noted that male F344 rats were far more sensitive
to tobramycin-induced nephrotoxicity. Similarly, a dose of 40 mg/kg gentamicin produced
nephrotoxicity in F344 rats while a dose of 70–100 mg/kg was required to induce an equivalent
adverse effect in Sprague-Dawley animals, and male F344 rats were more susceptible than females
to gentamicin-induced renal damage (Goodrich and Hottendorf, 1995; Sugarman et al., 1983; Kacew,
1989; Kacew and Bergeron, 1990). Sullivan et al. (1987) reported that Sprague-Dawley rats were more
resistant to the nephrotoxic and ototoxic effect of gentamicin than F344 animals. A decreased
susceptibility to the nephrotoxic action of gentamicin in Sprague-Dawley rats was supported by the
observation that proteinuria occurred after 4 din Wistar rats, whereas in Sprague-Dawley animals
9-10 d was needed to produce this adverse effect (Smetana et al., 1988, 1992). It should be noted
that F344 rats are more prone to severe, progressive renal disease (Goodman et al., 1994) than
other strains under normal aging processes. Thus, in the presence of drugs it is not surprising
that F344 rats are more susceptible to nephrotoxicants, and this factor needs to be considered in
assessing human risk from data based on this strain.
The importance of renal function markers in a
rat strain as an index of exposure was proposed by Bowers et al. (1992). A consistently low urinary
excretion rate of porphyrin was found in F344 rats, while in Sprague-Dawley animals this rate was
considerably higher and variable. Determination of individual urinary porphyrin concentrations
revealed that the inconsistencies observed in total porphyrin levels in Sprague-Dawley rats were
attributed primarily to differences in coproprophyrin concentrations, whereas in F344 rats the
coproprophyrin amounts in urine were continuously low. It is possible that the strain-related
differences are associated with variation in the regulation or metabolism of coproprophyrinogen
between strains. In addition, F344 rats appear most suitable to utilize as a biomarker for
environmental chemical exposure when urinary porphyrin excretion rate is an index of toxicity.
Although comparative drug-induced effects on porphyrin excretion have not been reported, it would
appear that the use of F344 strain rats might provide more meaningful data as a marker for toxicity.
LUNG
The use of amiodarone as an antiarrhythmic agent is limited due to the development of
pulmonary toxicity characterized by phospholipidosis, interstitial pneumonitis, and fibrosis in
humans and animals (Reasor and Kacew, 1991). Treatment with amiodarone at doses below 175 mg/kg
was found to induce a marked phospholipid accumulation in lung and alveolar macrophages
selectively in F344 rats bot failed to produce any effect in Sprague-Dawley, Long-Evans, or Wistar
animals (Mazue et al., 1984; Reasor et al., 1988). While no effect was seen in Wistar rats,
amiodarone (175 mg/kg) produced an abnormal lung lavage white blood cell count characterized by an
increased number of lymphocytes, neutrophils, and macrophages, and was significantly more
cytotoxic to fibroblasts and endothelial cells of F344 rats (Wilson and Lippmann, 1990).
Amiodarone in doses of 200 mg/kg or greater caused a considerable weight loss and morbidity in
F344 and Sprague-Dawley rats (Reasor et al., 1988). A dose of 175 mg/kg amiodarone produced
pulmonary toxicity in F344 rats without any apparent change in pulmonary inflammation in Wistar
rats (Wilson and Lippmann, 1990). However, with a twofold increase in amiodarone dose
(300–500 mg/kg), Wilson et al. (1991) reported the presence of pulmonary inflammation and
phospholipidosis in Wistar rats. Although the physiological status of these high-dosed animals
was not reported, data show that at equivalent low doses, the F344 rats are far more susceptible
to amiodarone-induced pulmonary toxicity. The observations that a metabolite of amiodarone,
desethylamiodarone, accumulated in the lungs and alveolar macrophages of F344, but not
significantly in Sprague-Dawley, Long-Evans, or Wistar, rats suggested that the metabolite was
involved in the drug-induced pulmonary toxicity (Reasor et al., 1989; Wilson and Lippmann, 1990).
Indeed, treatment of F344 rats with desethylamiodarone was found to induce phospholipidosis and
was more cytotoxic to fibroblasts and endothelial cells compared to amiodarone (Reasor et al.,
1988; Wilson and Lippmann, 1990). Although the susceptible F344 strain was not examined, Daniels
et al. (1990) confirmed that intraperitoneal administration of amiodarone was not effective in the
induction of pulmonary fibrosis in Sprague-Dawley rats, and this was associated with no apparent
change in the lung and liver microsomal mixed-function oxidase system. Treatment of Sprague-Dawley
rats with amiodarone resulted in the formation of an inactive cytochrome P-450 Fe(II)-metabolite
complex (Larrey et al., 1986). Thus in F344 responsive rats the cytochrome P-450 Fe(II) metabolite
is either not generated or the quantity of metabolite formed exceeds the inactivating complex such
that phospholipidosis is observed. The differences in amiodarone-induced phospholipidosis between
strains may also be related to dispositional factors, where the drug reached sufficient
concentrations to produce an effect only in lungs of F344 rats (McCloud et al., 1995).
At present evidence indicates that the
metabolite desethylamiodarone plays a role in amiodarone-induced pulmonary toxicity and this
phenomenon is strain-related. Several investigators demonstrated that the microsomal cytochrome
P-450 system is involved in the formation of desethylamiodarone (Rafeiro et al., 1990; Young and
Mehendale, 1986). In particular, it is the hepatic microsomal cytochrome P-450 system that is
responsible for amiodarone biotransformation to desethylamiodarone, as lung microsomes produced
negligible amounts of the active metabolite. Strain-related differences in the biotransformation
to desethylamiodarone may account for the observed differences in response to amiodarone. In a
recent study, Pirovino et al. (1990) clearly demonstrated that the amiodarone-induced pulmonary
phospholipidosis was associated with a significant increase in the activities of hepatic
microsomal cytochrome P-450 and NADPH cytochrome c reductase, and with an elevation in serum
desethylamiodarone in DA strain rats. In contrast, a lack of effect on morphology and phospholipid
content was accompanied by no marked change in the microsomal mixed-function oxidase system in
amiodarone-treated Sprague-Dawley rats. Hepatic microsomes derived from Sprague-Dawley rats and
incubated with amiodarone are capable of inducing the cytochrome P-450 system (Rafeiro et al.,
1990; Young and Mehendale, 1986); however, this does not occur in vivo. As suggested by Larrey et
al. (1986) in the Sprague-Dawley stock, induction of the hepatic microsomal mixed-function oxidase
system by amiodarone yields a metabolite that is inactivated, bot in the F344 rats the metabolite
formed is different and is active.
Monocrotaline, a pyrrolizidine alkaloid,
produces a pulmonary vascular disorder characterized by proliferative pulmonary vasculitis,
pulmonary hypertension, and cor pulmonale in Sprague-Dawley rats. However, Pan et al. (1993)
demonstrated that F344 rats were more resistant to monocrotaline-induced vascular damage, as
evidenced by lower histopathology lesion scores and less change in vessel cross-sectional diameter
than in Sprague-Dawley rats. Further monocrotaline significantly increased right ventricular
pressure in Sprague-Dawley bot not in F344 rats. Since the monocrotaline metabolite monocrotaline
pyrrole, believed to be the active component generated by hepatic microsomal enzymes, also
produces greater changes in Sprague-Dawley rats, this indicates the observed differences were due
to pulmonary vascular responsiveness rather than varying liver metabolism
(Table 3).
MAMMARY GLAND
The susceptibility of mammary gland to chemical-induced tumorigenesis has been well-documented (Goodman et al., 1994). As the focus of this review deals with naturally occurring and pharmaceutical agents, chemicals such as polycyclic aromatic hydrocarbons, atrazine, etc. are not considered even though marked strain-related responses have been reported. As early as 1947 Dunning et al. reported on the ability of diethylstilbesterol, used to prevent miscarriage in pregnant women, to induce mammary tumors in F344 rats. In a subsequent study, Dunning et al. (1953) found that diethylstilbesterol or estrone was equally effective in inducing mammary tumors in F344 and ACI strains but that the COP rat strain was resistant. Although mammary tumors were not present in COP rats, there was a higher incidence of urinary bladder calculi and adrenal tumors and reduced survival rate in comparison to F344 rats. Subsequently, Shellabarger et al. (1978) found that Sprague-Dawley rats, which are commonly used for carcinogenesis screening, were also resistant to the induction of mammary tumors, though the same dose induced over 70% mammary tumors in ACI strain rats. It is not clear how the tragic treatment of pregnant women with DES in the 1960s, which resulted in some of their daughters developing vaginal tumors when they reached puberty (Lynch and Reich, 1985), occurred, in view of the results of Dunning et al. (1953). However, it seems clear from these results that carcinogenesis screening based on the use of a single inbred strain or outbred stock may provide poor-quality data for assessing human risk. It is possible to incorporate more than one strain of animals into existing experimental designs for carcinogenesis screening without increasing the total number of animals or paying any statistical penalty for doing so (Festing, 1995).
URINARY BLADDER
The susceptibility of urinary bladder to natural product or drug-induced carcinogenesis is strain dependent. Ingestion of 5% sodium saccharin for 36 wk resulted in moderate histopathologic changes (pleomorphic microvilli, leafy microridges) in urinary bladder of Wistar rats (Fukushima et al., 1983). In F344, urinary bladder changes were slight but Sprague-Dawley rats were not affected. Ingestion of the plant bracken fern, which is sometimes used as a salad green or a food delicacy, resulted in a higher incidence of bladder tumors in F344 compared to Sprague-Dawley rats (Pamukcu et al., 1980). Garland et al. (1989) also found that Sprague-Dawley rats were more resistant than F344 to the cellular proliferative effects of saccharin on urinary bladder. Similarly, ingestion of N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in the drinking water for 32 wk increased the incidence of urinary bladder carcinoma to the greatest extent in ACI followed by Wistar, Sprague-Dawley, and LEW strains. In a subsequent study, Mori et al. (1987) included sodium ascorbate in the diet of rats drinking BBN. There was a three- and twofold higher incidence of urinary papilloma and carcinoma, respectively, in F344 animals than in LEW rats indicating that strain differences exist with respect to the sodium ascorbate tumor-promoting effect. In contrast to the Mori et al. (1987) study, saccharin does not appear to be metabolized; thus, it was proposed that other factors such as a chemical-induced change at the gene locus to initiate RNA synthesis and tumorigenic bladder cells may account for the differences in urinary bladder susceptibility to this agent between rat strains (Fukushima et al., 1983). In a comparison of three strains of rats, Dunning et al. (1953) found that estrone induced urinary bladder calculi formation and carcinoma by a fourfold higher incidence in COP than ACI or F344 rats. Further, the estrone-induced formation of bladder calculi and carcinoma in the COP and ACI strains was markedly greater in males compared to females. In the majority of cases males appear more prone to chemical-induced carcinoma (Goodman et al., 1994), hepatotoxicity (Pohl et al., 1984), and renal damage (Boorman et al., 1992), and this is similar to the phenomenon seen in the urinary bladder. The role of hormones in drug-induced urinary bladder carcinogenesis has still not been established.
DUODENUM AND PANCREAS
Treatment with the anti-inflammatory drug mepirizole produced duodenal ulcers and gastric
erosion in four strains of rats; however, there were marked differences in the incidence among the
strains (Ishihara et al., 1983). Whereas mepirizole-induced a high (100%) duodenal ulcer incidence
in Sprague-Dawley and F344 rats, a lower incidence of 90% was found in Wistar and 75% in DONRYU
rats. The gastric erosion index incidence was greater (95%) in F344 rats than in Sprague-Dawley,
Wistar, or DONRYU rats (80%). Mepirizole did not induce duodenal ulcers or gastric erosion in
mongrel dogs, Hartley guinea pigs, or ddy mice (Ishihara et al., 1983). Dietary ingestion of an
extract of bracken fern induced a significantly higher incidence of intestinal tumors in F344 than
in Sprague-Dawley rats (Pamukcu et al., 1980). The finding that ulceration or carcinoma was present
in both strains but differed in degree of severity suggests the underlying differences in
susceptibility may be related to pharmacokinetic variables or biochemical differences.
Edible mushrooms contain hydrazines that were
found to produce colonic carcinoma in rodents resembling human polyposis of the colon (Takizawa et
al., 1978). Treatment of Long-Evans rats with dimethylhydrazine produced an increased incidence and
number of colonic tumors. However, WF rats were resistant to colonic tumor formation, suggesting
that dimethylhydrazine may not be metabolized to a proximate carcinogenic in the gut or that the
immunologic reactivity differs between strains. It would appear that there may be a genetic
predisposition in susceptibility to hydrazine-induced colon tumors in rats similar to that found
in mice (Evans et al., 1977).
The antineoplastic agent azaserine induced
pancreatic atypical acinar cell nodules, which are preneoplastic lesions and may develop into
adenocarcinomas (Roebuck and Longnecker, 1977). The strains most susceptible to azaserine-induced
atypical acinar cell nodules in the pancreas were Wistar and W/LEW at 100% and 90% incidence rate,
respectively, whereas only 10% of F344 rats developed pancreatic carcinoma. It is of interest that
the susceptibility to azaserine-induced pancreatic dysfunction was twice as high in males compared
to females in all strains.
Betel nut chewers exhibit a high incidence of
oral cavity carcinoma believed to be related to the release of nitrosoguvacoline (NG) (Hoffmann et
al., 1994). Ingestion of NG in the drinking water at 1.9 mmol produced pancreatic tumors in F344
rats without an associated effect in Sprague-Dawley rats (Lijinsky and Taylor, 1976; Rivenson et
al., 1988). The responsiveness of the pancreas to drugs or naturally occurring substances does
depend on the strain examined, but a more precise interpretation can only be obtained when
experimental conditions are standardized.
ADIPOCYTES
It is well known that adipose tissue lipolysis is triggered by b-adrenergic receptor agonists including isoproterenol. Treatment of white adipocytes obtained from Wistar and Sprague-Dawley rats with isoproterenol stimulated lipolysis to the same extent (van Liefde et al., 1994). A similar response was noted with b-adrenoceptor antagonist dl-4-3[(1,1-dimethylethyl) amino]- 2-hydroxylpropoxy]-1,3-dihydro-2H-benzimidazol-2-one hydro-chloride (CGP12177) in the drug’s ability to suppress lipolysis in these two rat stocks. However, CGP12177 in the presence of isoproterenol inhibited lipolysis in Sprague-Dawley rats but not Wistar animals. Van Liefde et al. (1994) suggested that the differences in responsiveness to drug-induced lipolysis were associated with the population of b-adrenoceptor subtypes where Wistar rats contained atypical adipocytes while Sprague-Dawley possessed both classical and atypical adipocytes. Since the calorigenic benefits of lipolysis are partially dependent on adrenergic stimulation, differences in receptor populations in adipose tissue may account for the differences in locomotor and behavioral activities between these stocks.PITUITARY GLANDS AND HYPOTHALAMUS
It is well established that prolonged administration of estrogen results in the induction of
pituitary tumors characterized by elevated serum prolactin levels (Meyer and Clifton, 1956).
Treatment with diethylstilbesterol was found to induce pituitary tumors as evidenced by
histopathology and by excessive prolactin formation in F344 (Kaplan and DeNicola, 1976) and ACI
(Holtzman et al., 1979) strain rats. In contrast, Holtzman and Sprague-Dawley strain rats were far
more resistant to pituitary tumor induction by estrogens (Holtzman et al., 1979; Moy and Lawson,
1992). It should be noted that diethylstilbesterol enhanced prolactin synthesis and serum levels,
and induced pituitary tumors in susceptible and resistant rat strains; however, pituitary growth
was 10-fold greater in F344 and ACI rats compared to no significant tissue growth in Holtzman and
Sprague-Dawley animals (Holtzman et al., 1979; Wiklund et al., 1981). This is supported by the
findings that a diethylstilbesterol-induced pituitary tumor of a specific size required 8 wk to
develop in F344 animals but needed as long as 9 mo to produce an equivalent growth in Holtzman
rats (Wiklund et al., 1981). As the ability to synthesize prolactin is similar in both strains, it
was suggested that the responsiveness of the pituitary to chemicals was associated with
strain-related differences in the type of prolactin released. In a recent study, Moy and Lawson
(1992) demonstrated that the pituitary gland of diethylstilbesterol-treated F344 rats released
significantly increased amounts of a highly bioactive form of prolactin while in Holtzman rats the
prolactin released was of a different type, that is, immunoreactive only. This would certainly
account for the increased pituitary growth and tumor size found in F344 rats but lacking in
Holtzman animals.
In addition to prolactin, the pituitary is
involved in secretion of adrenocorticotropin hormone (ACTH) in response to hypothalamic
corticotropin-releasing factor (CRF). Treatment of LEW rats with a streptococcal cell wall
polysaccharide (SCW) produced an inflammatory reaction accompanied by decreased CRF, ACTH, and
corticosterone responses (Sternberg et al., 1992). In contrast, F344 rats appeared resistant to
the inflammatory and pituitary effects attributed to SCW, while Sprague-Dawley rats were
intermediate in the response observed. An acute startle stimulus increased corticosterone levels
fivefold in F344 and twofold in Sprague-Dawley without a marked effect in LEW rats (Glowa et al.,
1992a). Similarly, administration of CRF produced a significant behavioral effect in F344 but not
LEW rats (Glowa et al., 1992b). Clearly, the hypothalamic pituitary axis function, which varies
between strains, is used as an index of susceptibility to inflammatory autoimmune diseases, and
this, would account for the observed differences in steroid function. LEW strain rats would thus
exhibit susceptibility to autoimmune disease and behavioral alterations, parameters affected by
corticosterone (Glowa et al., 1992a).
Rodent behavior, including locomotion,
sensory, etc., is partially dependent on hypothalamic regulation of body temperature.
Thermoregulation has been shown to act as a sensitive system in the assessment of toxicant actions
on the central nervous system (CNS) (Gordon et al., 1988). Rats in general prefer a lower ambient
room temperature compared to other species. However, there are marked rat strain-related
differences in the ambient temperature preferred with Long-Evans, F344, and Sprague-Dawley at
preferring 19.8, 23.4, and 24.9 °C, respectively, which may be related to the fact that
Sprague-Dawley rats have a larger body mass (Gordon, 1987). As ambient temperature was raised to
34 °C, the colonic temperature exceeded 38 °C in Long-Evans and Sprague-Dawley rats. An
ambient temperature of 36 °C was required to produce a significant elevation in F344 colonic
temperature, indicating that F344 rats had a better ability to dissipate heat by evaporation.
PERIPHERAL AND CENTRAL NERVOUS SYSTEM
The nitrosoureas are a class of antitumor drugs that were shown to be effective in a variety
of human malignancies. Treatment of 1-d old neonates with ethyl-N-nitrosourea produced brain tumors
to a similar 98% extent in all four rat strains, WF, Long-Evans, WF/LE (F1), and F344,
within 6 mo (Naito et al., 1982). However, in the peripheral nervous system (cranial verve, spinal
root), ethyl-N-nitrosourea induced a 93% tumor incidence in Long-Evans rats but only approximately
15% in F344 and WF strain rats. Although the basis for this strain-dependent effect is not known,
it is of interest that 1,2-dimethyl-hydrazine produced a higher incidence of colon carcinoma in
Long-Evans compared to WF strain rats (Takizawa et al., 1978).
The behavioral responsiveness of rats to
drugs and external stimuli is strain dependent
(Table 4). In an extensive study, Glowa and
Hansen (1994) found a marked difference in both the amplitude to an acoustic startle stimulus and
the rate of habituation to startle stimuli among 46 rat strains. Further work is needed to
determine the physiological and biochemical basis of these differences.
Prepulse inhibition (PPI) of the acoustic
startle reflex is utilized as a model of sensorimotor gating deficits in animals, and disruption in
PPI is characteristic of human schizophrenia (Geyer et al., 1990). Treatment with apomorphine
disrupted the PPI in Wistar rats, while in Sprague-Dawley animals there was no observable response
(Rigdon, 1990). Although the basis for this stock-dependent effect is not known, it is evident that
the choice of Wistar strain rats would be more suitable as a model to investigate mechanisms
underlying schizophrenia.
Table 4. Strain-related central nervous system responses
|
|
Strain/stock |
|
|
|
Parameter |
Resistant a |
Susceptible |
Reference |
|
SCW-induced hypothalamic CRF secretion |
|
|
|
|
Acute startle stimulus increase in corticosterone |
|
|
|
|
CRF-induced open-field behavior |
LEW |
F344 |
Glowa et al. (1992b) |
|
Body temperature adaptation |
F344 |
Sprague-Dawley |
Gordon et al. (1988) |
|
Apomorphine disruption of prepulse inhibition |
|
|
|
|
Morphine-induced antinoception |
Sprague-Dawley |
F344 |
Rosecrans et al. (1986) |
|
Footshock-induced analgesia |
Sprague-Dawley |
F344 |
Rosecrans et al. (1984) |
|
Imipramine-induced decrease in immobility (despair) |
Sprague-Dawley |
Wistar F344 |
Porsolt et al. (19786) |
|
Naloxone attenuation of footshock analgesia |
|
|
|
|
Cocaine-induced increase in locomotor activity |
LEW or F344 |
NBR F344 |
George et al. (1991) |
|
Amphetamine-induced increase in locomotor activity |
|
|
|
|
Ethanol preference and behavior activation |
ACI F344 |
MR LEW |
Li and Lumeng (1984) |
a
Resistant does not imply a lack of effect but a significantly lower incidence than in susceptible.
Strain-associated differences between
Sprague-Dawley and F344 rats have also been reported where the F344 animals appear behaviorally
less active in runway learning and shuttle-box learning, the turnover of forebrain serotonin is
slower, and the responsiveness to morphine-induced antinociception is increased compared to
Sprague-Dawley rats (Rosecrans et al., 1986). With the use of a continuous footshock stimulation
regime (non-opioid), Rosecrans et al. (1984) demonstrated that induction of analgesia occurred
sooner and was greater in F344 rats in both restrained and free-moving conditions but that
analgesia could only be induced in Sprague-Dawley rats when there was restraint, indicating that
F344 rats were markedly more sensitive. In F344 rats analgesia was accompanied by a significant
increase in plasma prolactin and plasma and adrenal corticosterone, while in Sprague-Dawley
animals only plasma corticosterone was elevated (Rosecrans et al., 1986). The higher levels of
dopamine and 5-hydroxytryptamine found in the hypothalamus and frontal cortex of F344 rats
suggested a slower turnover rate for these mediators and a decreased ability to respond to stress
compared to Sprague-Dawley rats. Although there are strain-related differences in the ability of
rats to respond to stress, the underlying basic mechanisms are poorly understood.
Imipramine is an effective drug used in the
treatment of depression. In order to simulate a depressive state, Porsolt et al. (1978a) forced
rats to swim in a restricted space without escape, and after an initial period of vigorous
activity, these animals adopt a characteristic immobile posture. In this latter state rats keep
their heads above water and this immobility is considered a state of despair. Porsolt et al.
(1978b) found no significant difference in the duration of immobility or despair in Sprague-Dawley
and Wistar rats, but in the presence of imipramine the duration of immobility was markedly reduced
in Sprague-Dawley animals. In a subsequent study Paul et al. (1990) also demonstrated that
Sprague-Dawley rats displayed behavioral adaptation (increased duration of immobility) to a prior
conditioning swim, whereas this behavioral response was absent in F344 rats. Further imipramine
treatment failed to reduce the duration of immobility in F344 rats, while a decrease was noted in
Sprague-Dawley animals. It is of interest that imipramine produced a similar decrease in
hippocampal and frontal cortex dihydroalprenol binding in Sprague-Dawley and F344 rats, suggesting
that the behavior and receptor changes are not related. Evidence thus indicates that there are
strain-related differences in the behavioral responses to imipramine.
Electric footshock to rats for 30 min with
intermittent stimulation produces an opioid, naloxone-sensitive analgesia; however, a 3 min
continuous shock results in a non-opioid, naloxone-insensitive form of analgesia (Lewis and
Liebeskind, 1980). In a study of various strains of rat, Urca et al. (1985) induced analgesia by
the use of footshock stress applied continuously, indicating that the non-opioid system was
activated regardless of strain. However, after 30 min of intermittent footshock, analgesia induced
in Sprague-Dawley rats was attenuated with naloxone but this was not the case in Wistar rats.
There are thus strain-related differences in opioid-mediated analgesia. Intermittent
footshock-induced opioid-mediated analgesia is associated with suppression of natural killer cells,
suggesting an involvement of the immune system, and this effect is blocked with naltrexone (Shavit
et al., 1984). It is thus conceivable that the analgesia-induced differences between Sprague-Dawley
and Wistar rats may be related to immunosuppression, including a decrease in natural killer cells
in the former, and this effect appears to be absent in the latter stock. In agreement with the
hypothesis that differences in immune responsiveness may account for variation in the
susceptibility or resistance to drugs and the consequent adverse effects occurring in other
tissues is the finding that only certain strains respond to amiodarone-induced phospholipidosis
(Wilson and Lippmann, 1990), SCW-induced inflammation (Sternberg et al., 1992), and
cyclophosphamide-induced pulmonary damage (Anton, 1993). In all these cases there is evidence of
immunosuppressive differences between strains. The use of mutant rats such as the athymic Rowett
nude (Festing, 1981) may help to clarify the role of the immune system in response to drugs.
The behavioral responsiveness of rodents to
drugs of abuse is strain dependent (Table 4).
At low (5–10 mg/kg) doses of cocaine there was
a significant increase in locomotor activity in NBR rats without a marked effect in LEW or F344
rats (George et al., 1991). As the cocaine dose was increased to 20 mg/kg, locomotor activity was
enhanced in LEW and F344 rats, but at this drug dose there was a sixfold higher stimulation in NBR
animals. With amphetamine at a dose of 10 mg/kg the LEW rats appeared insensitive, while
significant locomotor activity was noted in F344 and NBR animals. When compared in rank order,
F344 rats responded least to cocaine with LEW rats least responsive to amphetamine (George et al.,
1991). Although there were differences in behavioral strain-related effects, dopamine receptor
binding and density, believed to be involved in locomotor activity, were similar in all rat
strains. However, in a recent study, Kosten et al. (1994) reported no significant difference in
locomotor activity and conditioned taste aversion to a single dose of cocaine between LEW and F344
rats. With repeated cocaine administration LEW rats displayed enhanced locomotor activity and
conditioned place preference, behavioral parameters not seen in F344 rats. In contrast to George
et al. (1991), Beitner-Johnson et al. (1991) found strain differences in mesolimbic dopaminergic
system between F344 and LEW rats: Despite the fact that the findings between these groups of
investigators appear inconsistent, it is clearly evident that rat strain is a factor in observed
behavioral responsiveness of rodents to drugs of abuse.
The rat has been used extensively in studies
of alcoholism and alcohol toxicity. Selection programs to develop high and low alcohol-accepting
strains have resulted in the development of the outbred CCh-B and CCh-A pair of strains in Chile in
the 1950s, the outbred AA and ANA in Helsinki in the 1960s, and the outbred P and NP pair in
Indianapolis in the 1970s. The use of these strains has been reviewed by Sinclair et al. (1992).
They show clearly that alcohol acceptance is under genetic control, and provide tools for studying
the biochemical/physiological mechanisms associated with alcohol acceptance. Several inbred strains
such as the TMB and the RHA (Drewek and Broadhurst, 1979) also exhibit high ethanol preference. In
a study of eight inbred rat strains, it was found that ACI rats did not prefer alcohol and
exhibited low alcohol consumption (Li and Lumeng, 1984). Wistar and F344 were intermediate in the
observed response, while the highest alcohol intake and preference was found in MR strain rats. The
MR strain was found to resemble the TMB and RHA strains in this alcohol-preference behavior. In a
subsequent comparative study between strains, Suzuki et al. (1988) demonstrated that LEW rats drank
more ethanol than F344 rats. This was associated with higher alcohol levels, a greater number of
ethanol self-deliveries, and behavioral activation in LEW but not F344 rats.
SUMMARY
A summary of tissue-specific strain-related differences in responses to drugs is presented in Table 5. In comparison to the existing pharmacopoeia of available therapeutic agents this list is small; however, in most research only one strain was used, so the potential extent of strain differences cannot be determined. This review suggests that strain differences of great toxicological significance such as complete resistance or susceptibility to a carcinogen are not unknown. Smaller strain differences, which may still be of toxicological interest and may even help to clarify mechanisms, may be quite common. This suggests that research and/or screening programs that use only a single strain may be unreliable as a means of providing data for human risk assessment because the outcome may depend entirely on the chance of which strain happened to be chosen. In some cases, if strain X is chosen the compound is classified as a non-carcinogen, but if strain Y is used it is classified as a carcinogen. Clearly, this is not very satisfactory. It would be more ideal if much more research involved more than one strain. It is sometimes assumed that such a strategy would be prohibitively expensive. Surely, if two or three strains are to be used, this will involve two or three times the number of animals? In fact, this is not the case. In many cases, it is possible to use more than one strain in an experiment with little or no increase in the total number of animals used, by using a “factorial” experimental design (Festing, 1993, 1995). This approach should substantially broaden knowledge of genotype in drug-induced effects.
Table 5. Strain-related differences in drug-induced responses
|
|
|
Strain/stock |
|
|
|
Parameter |
Tissue |
Resistant a |
Susceptible |
Reference |
|
Ciprofibrate-induced peroxisomal proliferation |
Liver |
Sprague-Dawley |
Long-Evans |
Makowska et al. |
|
Bezafibrate-induced peroxisomal proliferation |
Liver |
Sprague-Dawley |
LEW |
Pill et al. (1992) |
|
Acetaminophen-induced necrosis |
Kidney |
Sprague-Dawley |
F344 |
McMurtry et al. |
|
Streptozotocin-induced autoimmune reactivity |
Popliteal |
F344 |
Sprague-Dawley |
Patriarca et al. |
|
Gentamicin-induced toxicity |
Kidney |
Sprague-Dawley |
F344 |
Kacew and |
|
Amiodarone-induced phospholipidosis |
Lung |
Sprague-Dawley |
F344 |
Reasor et al. |
|
Diethylstilbesterol-induced carcinoma |
Mammary |
COP |
F344 |
Dunning et al. |
|
Saccharin-induced histopathologic changes |
Urinary |
Sprague-Dawley |
Wistar |
Fukushima et al. |
|
Mepirizole-induced ulceration |
Duodenum |
DONYRU |
Sprague-Dawley |
Ishihara et al. |
|
Azaserine-induced carcinoma |
Pancreas |
F344 |
Wistar |
Roebuck and |
|
b-Adrenoceptor suppression of lipolysis |
Adipocyte |
Wistar |
Sprague-Dawley |
van Liefde et al. |
|
Diethylstilbesterol-induced prolactin section |
Pituitary |
Sprague-Dawley |
F344 |
Holtzman et al. |
a
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