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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