Effect of inter-individual variability in human liver cytochrome P450 isozymes on cyclophosphamide-induced micronucleus formation

Publication date: Available online 5 December 2018Source: Mutation Research/Genetic Toxicology and Environmental MutagenesisAuthor(s): Yuki Kishino, Tomoko Hasegawa, Ayako Kato, Yumi Nishiya, Veronika Rozhnal, Kyoko Watanabe, Wataru Takasaki, Takashi Yamoto, Kazuhiko MoriAbstractWe investigated the relationship between metabolic activities of cytochrome P450 (CYP) isozymes present in microsomal fractions derived from the livers of 78 donors and micronucleus induction by cyclophosphamide (CPA). Consequently, a wide inter-individual variation in CYP activities was observed among the 78 donors. The CYP activities were partially correlated with the metabolic phenotypes predicted for the donors based on their single nucleotide polymorphisms. In addition, CPA induced micronucleus formation was seen for 47 out of 52 donors whose samples were tested with CPA doses ranging from 18.8 to 100 μg/mL. The CPA dose at which micronucleated cells were observed varied among the donors. Furthermore, a close correlation was identified between the catalytic activities of the CYP2B6, CYP2C9, CYP2C19, and CYP3A4 isozymes and micronucleus induction by CPA. To elucidate the mechanism underlying CPA-induced micronucleus formation in vitro tests were conducted on expression systems of CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Additionally, the metabolites of CPA generated by the expression systems were quantified by a liquid chromatography tandem mass spectrometer. Interestingly, several metaboli...
Source: Mutation Research Genetic Toxicology and Environmental Mutagenesis - Category: Genetics & Stem Cells Source Type: research