Species differences in micronucleus induction of the clastogenic compounds associated with drug metabolic profile.

Abstract

Genotoxicity and carcinogenicity profiles of drugs occasionally vary across species due to species difference in drug metabolic profile. To clarify the effect of species differences in the metabolic profile on micronucleus induction, we conducted an in vitro micronucleus test for seven clastogens (benzo[a]pyrene: BaP, cyclophosphamide monohydrate: CPA coumarin, diclofenac, piroxicam, lansoprazole, and chlorpheniramine) with rat, mouse, monkey, dog, or human liver S9. BaP, CPA, coumarin, diclofenac, piroxicam, and lansoprazole induced micronucleus formation with all species of S9s, whereas chlorpheniramine did not induce micronucleus formation in any of the S9s. BaP and CPA revealed remarkable species differences in micronucleus induction, whereas coumarin, diclofenac, piroxicam, and lansoprazole did not present any differences. Interestingly, the amounts of hydroxy-BaP-epoxides and phosphamide mustard, which might be associated with micronucleus induction by BaP and CPA, respectively, were correlated with the degree of micronucleus induction among the five species. In conclusion, the species difference in micronucleus induction by BaP and CPA was attributable to the differences in the metabolic profiles of these drugs among species. Our results indicate that it is crucial to understand the effect of species differences in the metabolic profile of drug candidates on genotoxicity and carcinogenicity potential and to predict their risk in human.