Effect of the metabolic capacity in rat liver S9 on the positive results of in vitro micronucleus tests

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  • Kishino Yuki
    Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
  • Hasegawa Tomoko
    Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
  • Arakawa Shingo
    Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
  • Shibaya Yukari
    Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
  • Yamoto Takashi
    Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
  • Mori Kazuhiko
    Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.

書誌事項

タイトル別名
  • Effect of the metabolic capacity in rat liver S9 on the positive results of <i>in vitro</i> micronucleus tests
公開日
2019
資源種別
journal article
DOI
  • 10.2131/jts.44.145
公開者
一般社団法人　日本毒性学会

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説明

<p>A high incidence of positive results is obtained with in vitro genotoxicity tests, which do not correlate with the in vivo 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 in vitro 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[a]pyrene (BaP), cyclophosphamide (CPA), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]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 in vivo 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 in vitro and in vivo metabolic profile and its exposure levels of the drugs.</p>

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