Invited Review
Role of Rat Strain in the Differential Sensitivity to Pharmaceutical Agents and
Naturally Occurring Substances*
S. Kacew1 and M. F. W. Festing2
1 Department of Pharmacology, University of Ottawa, Ottawa, Ontario, Canada
2 MRC Toxicology Unit, University of Leicester, Leicester, United Kingdom
Corresponding author: Dr. S. Kacew
Department of Pharmacology, University of Ottawa
451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada
* Reprinted with permission from J. Toxicol. Environ. Health, 47:1-30, 1996
CEJOEM 1999, Vol.5. No.3-4.:201-231
Key words:
Chemicals, pharmaceutical agents, metabolism, sensitivity, drug
Abstract:
The development of drugs to combat diseases, chemicals to improve
food production or compounds to enhance the quality of life necessitates, by law, the
use of laboratory animals to test their safety. In order to simulate the human condition
it is necessary to choose a species in which pharmacokinetic and toxicokinetic mechanisms
are established and resemble those of humans. The advantages of the use of the rat in
drug and chemical toxicity testing include (a) metabolic pathway similarities to humans;
(b) numerous similar anatomical and physiological characteristics; (c) a large database,
which is extremely important for comparative purposes; and (d) the ease of breeding and
maintenance of animals at relatively low cost. However, the choice of rat can be
complicated, especially when over 200 different strains of rat are known to exist.
The aim of this review is to summarize genetically determined differences in the
responsiveness of rat strains to drugs and naturally occurring chemicals and to show
that susceptibility is dependent on the target organ sensitivities, which may also
be strain dependent. It is suggested that detailed studies of strain differences may
help to clarify toxic mechanisms. Such studies are usually best conducted using inbred
strains in which the genetic characteristics have been fixed, rather than in outbred
stocks in which individual samples of animals may differ, the phenotype is variable,
and the stocks are subject to substantial genetic drift. The fact that strains may
differ also needs to be taken into account in assessing the potential hazard of the
chemical, particularly when a study involves only a single strain and therefore provides
no assessment of likely strain variation.
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