1 School of Biomedical Sciences, University of Queensland, St Lucia, QLD 4072, Australia ; 2 Centre for Kidney Disease-Venomics Research, School of Medicine, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, QLD 4102, Australia.
Ann Transl Med. 2014 Jan;2(1):7. doi: 10.3978/j.issn.2305-5839.2013.03.02.
CYP3A4 is a major cytochrome P450. It catalyses a broad range of substrates including xenobiotics such as clinically used drugs and endogenous compounds bile acids. Its function to detoxify bile acids could be used for treating cholestasis, which is a condition characterised by accumulation of bile acids. Although bile acids have important physiological functions, they are very toxic when their concentrations are excessively high. The accumulated bile acids in cholestasis can cause liver and other tissue injuries. Thus, control of the concentrations of bile acids is critical for treatment of cholestasis. CYP3A4 is responsively upregulated in cholestasis mediated by the nuclear receptors farnesol X receptor (FXR) and pregnane X receptor (PXR) as a defence mechanism. However, the regulation of CYP3A4 is complicated by estrogen, which is increased in cholestasis and down regulates CYP3A4 expression. The activity of CYP3A4 is also inhibited by accumulated bile acids due to their property of detergent effect. In some cholestasis cases, genetic polymorphisms of the CYP3A4 and PXR genes may interfere with the adaptive response. Further stimulation of CYP3A4 activity in cholestasis could be an effective approach for treatment of the disease. In this review, we summarise recent progress about the roles of CYP3A4 in the metabolism of bile acids, its regulation and possible implication in the treatment of cholestasis.
CYP3A4 是一种主要的细胞色素 P450。它催化广泛的底物，包括外源性药物和内源性化合物胆汁酸等。其对胆汁酸的解毒作用可用于治疗胆汁淤积症，胆汁淤积症的特征是胆汁酸积累。虽然胆汁酸具有重要的生理功能，但当其浓度过高时，它们非常有毒。胆汁淤积症中积累的胆汁酸会导致肝脏和其他组织损伤。因此，控制胆汁酸的浓度对于治疗胆汁淤积症至关重要。CYP3A4 在核受体法尼醇 X 受体 (FXR) 和孕烷 X 受体 (PXR) 介导的胆汁淤积中作为防御机制被响应性地上调。然而，由于雌激素在胆汁淤积症中增加并下调 CYP3A4 表达，因此 CYP3A4 的调节变得复杂。由于其去污剂的特性，积累的胆汁酸也会抑制 CYP3A4 的活性。在一些胆汁淤积症病例中，CYP3A4 和 PXR 基因的遗传多态性可能会干扰适应性反应。进一步刺激胆汁淤积症中 CYP3A4 的活性可能是治疗该疾病的有效方法。在这篇综述中，我们总结了 CYP3A4 在胆汁酸代谢、其调节及其在胆汁淤积症治疗中的可能作用的最新进展。
