The role of CYP3A4 in the biotransformation of bile acids and therapeutic implication for cholestasis

Abstract

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.

Keywords: CYP3A4; bile acids; cholestasis; detoxification; nuclear receptors.

Figure 1

Regulation of CYP3A4. CYP3A4 is stimulated by nuclear receptors (PXR, FXR, CAR), hormones, xenobiotics and HNFs. It is inhibited by xenobiotics and signalling molecules Stat3 and NF-κB. Increased CYP3A4 activity results in increased bile acids detoxification and drug deactivation. Abbreviations: FXR, farnesol X receptor; PXR, pregnane X receptor; CAR, constitutive androstane receptor; HNF, Hepatic nuclear factor; Stat3, signal transducer and activator of transcription 3 and NF-κB nuclear factor kappa beta.

Figure 2

Biotransformation of bile acids by CYP3A4. CYP3A4 transforms CA into 3-dehydro-CA, CDCA into Hyocholic Acid and 3α, 7α -dihydroxy-3-oxo-5β-cholanoic acid, DCA into 1β-hydroxy-DCA and 3-dehydro-DCA and LCA into hyodeoxycholic acid, 1β-hydroxy-LCA, 3-dehydro-LCA and 6α-hydroxy-3-oxo-5β-cholanoic acid. Abbreviations: CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; LCA, lithocholic acid.