During its evolution, every animal species was under an individual selection pressure with regard to drug metabolism, in major part dictated by its preferred diet. Thus, some major species differences in drug metabolism68,69 may tentatively be rationalized by species-specific requirements. Cats are exclusively carnivores. They almost completely lack the ability to glucuronidate xenobiotics, presumably because they do not have a need to render the easily glucuronidatable plant flavonoids or alkaloids excretable. For less obvious reasons, pigs are slow in drug sulfation and dogs are poor acetylators. The rat has extremely low levels of sEH in the liver.
It is important to choose the appropriate animal species for the analysis of the metabolism of a drug, in order to make predictions for metabolism-dependent toxicities in man. An impressive example of wrong predictions concerning toxification versus detoxification was the use of cynomolgus monkeys as an animal species closely related to man in the assessment of the carcinogenicity of heterocyclic amines present in cooked meat. Cynomolgus monkeys do not possess the heterocyclic amine toxifying CYP1A2. Thus, the study gave false-negative results. In contrast, these heterocyclic amines were potent carcinogens in the marmoset, a primate with a significant level of CYP1A2.
Toxicologically important species differences also occur in the regulation of enzyme expression. Peroxisome proliferators lead to an increase in the number and size of peroxisomes. Peroxisomal beta-oxidation, which produces hydrogen peroxide, is induced together with several drug-metabolizing enzymes by peroxisome proliferators. Treatment of rodents with peroxisome proliferators led to hepatocellular carcinomas. Peroxisome proliferation, the putative reason for the increased liver cancer incidence, did not occur to a significant extent in humans. Therefore, the peroxisome-proliferating hypolipidemic fibrates, which induce liver cancer in rodents, are rightfully still used in human therapy.
Since drug metabolism takes place predominantly in the liver, primary hepatocytes from experimental animal species and from man are often good predictors of drug metabolism-dependent drug toxicities and hence also of the best choice of an animal model for metabolism-dependent drug toxicities.70'71 An example is the stomach parietal cell proton pump inhibitor pantoprazole that caused death in dogs by formation of the toxic benzimidazourea, which was formed by dog but not by human hepatocytes.68 An additional excellent model is that of 'humanized' mice in which genes coding for individual xenobiotic metabolizing enzymes have been knocked out and replaced by related human genes.72
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