Gillani Tina B, Rawling Tristan, Murray Michael
Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, University of Sydney , Sydney, NSW 2006, Australia.
School of Pharmacy, Graduate School of Health, University of Technology, Sydney , PO Box 123, Broadway, Ultimo, NSW 2007, Australia.
Chem Res Toxicol. 2015 Jan 20;28(1):92-102. doi: 10.1021/tx500373g. Epub 2014 Dec 23.
The multikinase inhibitor sorafenib (SRF) is approved for the treatment of renal and hepatic carcinomas and is also undergoing evaluation in therapeutic combinations with other anticancer agents. SRF is generally well tolerated but produces severe toxicities in a significant proportion of patients by mechanisms that are largely unknown. It has been shown that cytochrome P450 (CYP) 3A4 has a major role in SRF biotransformation to the pharmacologically active N-oxide (SRF-Nox) and two other metabolites. In this study, we prepared the major metabolites of SRF and evaluated their further biotransformation by CYPs in relation to their capacity to produce cellular toxicity. CYP3A4 was also found to be the principal enzyme that mediated the secondary oxidation of SRF metabolites. However, the reduction of SRF-Nox to SRF was also found to be a significant reaction mediated by several CYPs, especially CYPs 2B6 and 1A1. In human liver-derived HepG2 cells, SRF effectively decreased ATP production to an extent greater than that of its metabolites. SRF also markedly altered the cell cycle distribution in HepG2 cells by decreasing the proportion in G0/G1 phase and increasing that in S and G2/M phases. In comparison, SRF metabolites minimally affected HepG2 cell cycle progression. These findings suggest that SRF, but not its metabolites, prevents cells from entering the cell cycle and also inhibits cycling cells from completing mitosis. Reduction of the major metabolite SRF-Nox back to SRF may mediate decreased cellular viability and contribute to adverse reactions in some individuals.
多激酶抑制剂索拉非尼（SRF）已被批准用于治疗肾癌和肝癌，并且正在与其他抗癌药物联合治疗中接受评估。SRF一般耐受性良好，但在很大一部分患者中会产生严重毒性，其机制大多未知。研究表明，细胞色素P450（CYP）3A4在SRF生物转化为药理活性N-氧化物（SRF-Nox）和其他两种代谢物的过程中起主要作用。在本研究中，我们制备了SRF的主要代谢物，并评估了它们在细胞毒性产生能力方面通过细胞色素P450的进一步生物转化。还发现CYP3A4是介导SRF代谢物二次氧化的主要酶。然而，SRF-Nox还原为SRF也被发现是由几种细胞色素P450介导的显著反应，尤其是细胞色素P450 2B6和1A1。在人肝源性HepG2细胞中，SRF有效降低ATP生成，其程度大于其代谢物。SRF还通过降低G0/G1期比例并增加S期和G2/M期比例，显著改变HepG2细胞的细胞周期分布。相比之下，SRF代谢物对HepG2细胞周期进程的影响最小。这些发现表明，SRF而非其代谢物可阻止细胞进入细胞周期，并抑制循环细胞完成有丝分裂。主要代谢物SRF-Nox还原回SRF可能介导细胞活力降低，并导致一些个体出现不良反应。
