Cytochrome P450 3A5 polymorphism affects the metabolism of sorafenib and its toxicity for hepatocellular carcinoma cells .

Objective: Cytochrome P450 3A5 () is a highly polymorphic gene and the encoded protein variants differ in catalytic activity, leading to inter-individual variation in metabolic ability. The aim of the current study was to investigate the effects of seven allelic variants on the ability of to metabolize sorafenib and further explore the impacts of polymorphism on the proliferation and apoptosis of hepatocellular carcinoma cell line (HepG2) induced by sorafenib.

Methods: Wild-type and variant CYP3A5 enzymes were expressed in insect cells using a baculovirus dual-expression system, and protein expression was checked by western blot. The enzymes were incubated with sorafenib at 37°C for 30 min, and formation of the major metabolite sorafenib -oxide was assayed using ultra-performance liquid chromatography and tandem mass spectrometry. Intrinsic clearance values /) were calculated for each enzyme. Additionally, recombinant HepG2 cells transfecting with variants were used to investigate the effects of sorafenib on the proliferation of HepG2 cells.

Results: Intrinsic clearance of the six variants , , , , and was 26.41-71.04% of the wild-type () value. In contrast, the clearance value of the variant was significantly higher (174.74%). Additionally, the decreased ATP levels and cell viability and the increased cell apoptosis in HepG2 cells transfected with , , , , , and were observed, whereas, the increased ATP levels and cell viability and the reduced cell apoptosis in HepG2 cells transfected with were also investigated when compared to .

Conclusion: Our results suggest that polymorphism influences sorafenib metabolism and pharmacotherapeutic effect in hepatic carcinomas These data may help explain differential response to drug therapy for hepatocellular carcinoma, and they support the need for individualized treatment.