Effect of the metabolic capacity in rat liver S9 on the positive results of <i>in vitro</i> micronucleus tests

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<p>A high incidence of positive results is obtained with <i>in vitro</i> genotoxicity tests, which do not correlate with the <i>in vivo</i> negative results in many cases. To address this issue, the metabolic profile of rat liver 9000 × g supernatant fraction (S9) pretreated with phenobarbital (PB) and 5,6-benzoflavone (BNF) was characterized. Furthermore, the <i>in vitro</i> micronucleus tests of 10 compounds were performed with PB-BNF-induced rat S9. PB-BNF increased cytochrome P450 (CYP) activity and CYP1A1, CYP1A2, CYP2B1/2, CYP2C6, CYP3A1, and CYP3A2 expression in rat S9, whereas it decreased CYP2C11 and CYP2E1 expression. PB-BNF-induced S9 enhanced the micronucleus induction (MI) of benzo[<i>a</i>]pyrene (BaP), cyclophosphamide (CPA), and 2-amino-1-methyl-6-phenylimidazo[4,5-<i>b</i>]pyridine hydrochloride (PhIP), which are metabolized by CYP1A1, CYP2C6, and CYP1A2, respectively. In contrast, coumarin and chlorpheniramine showed MI with PB-BNF-induced S9 despite the fact that they show negative results in the <i>in vivo</i> studies. Furthermore, diclofenac, piroxicam, lansoprazole, and caffeine showed MI regardless of the enzyme induction by PB-BNF, whereas phenacetin did not show MI. These results indicate that PB-BNF-induced rat S9 is effective in detecting the genotoxic potential of promutagens, such as BaP, CPA, and PhIP, but not of coumarin and chlorpheniramine, probably due to the differences in the <i>in vitro</i> and <i>in vivo</i> metabolic profile and its exposure levels of the drugs.</p>


  • The Journal of Toxicological Sciences

    The Journal of Toxicological Sciences 44(3), 145-153, 2019

    The Japanese Society of Toxicology


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