1576

CYP3A4

cytochrome P450, family 3, subfamily A, polypeptide 4;CYP3A4;cytochrome P450, family 3, subfamily A, polypeptide 4

1,8-cineole 2-exo-monooxygenase|P450-III, steroid inducible|albendazole monooxygenase|albendazole sulfoxidase|cytochrome P450 3A3|cytochrome P450 3A4|cytochrome P450 HLp|cytochrome P450 NF-25|cytochrome P450, subfamily IIIA (niphedipine oxidase), polypept

7q21.1

protein-coding

AIM: To examine how the higher expression level of CYP3A4 isoenzyme influenced the cytotoxicity of the antitumor triazoloacridinone derivative C-1305 in Chinese hamster ovary (CHO) cells. METHODS: Three CHO cell lines were examined: wild-type CHO cells; CHO-HR cells with overexpression of human cytochrome P450 reductase (CPR); and CHO-HR-3A4 cells with coexpression of human CYP3A4 and CPR. cellular responses caused by C-1305 were monitored using DAPI staining, cell cycle analysis, phosphatydilserine externalization analysis and SA-beta-galactosidase expression analysis. cell viability was assessed with simultaneous FDA and PI staining. RESULTS: Treatment with C-1305 for 72 h exhibited different levels of cytotoxicity in the 3 cell lines, and the values of IC80 in CHO, CHO-HR and CHO-HR-3A4 cells were 0.087+/-0.005, 0.032+/-0.0001, and 0.064+/-0.0095 mumol/L, respectively. The cell cycle analysis revealed that both CHO and CHO-HR cells underwent transient G(2)/M arrest, whereas CHO-HR-3A4 cells did not accumulate in this phase. Prolonged exposure up to 120 h caused time-dependent increase in the sub-G(1) fraction in ALL the 3 cell lines. Treatment with C-1305 caused cell death through apoptosis and necrosis. However, these processes were more pronounced in the transfected CHO cells than in the wild-type cells. The cells surviving after C-1305 exposure underwent senescence. CONCLUSION: CYP3A4 overexpression potently enhances the cellular responses (apoptosis, necrosis and senescence) caused by C-1305 in CHO cells.