Bile acid regulation of drug metabolism

From LipidomicsWiki

It has been known for a long time that PCN affects microsomal metabolism of steroids and bile acids in rodents (Einarsson and Gustafsson 1973, 1974). PCN and dexamethasone markedly reduce CYP7A1 gene expression in rat livers (Chiang et al. 1990; Li et al. 1990). Recent studies of Pxr null mice have uncovered a link between bile acids and drug metabolism (Staudinger et al. 2001; Xie et al. 2001). PXR is activated by a large number of endogenous and exogenous compounds including steroids, drugs, and secondary bile acids (LCA and CDCA). PXR induces CYP3A family of enzymes involved in the metabolism of a wide variety of drugs and xenobiotics in the liver and intestine (Goodwin and Kliewer 2002; Goodwin et al. 2003; Dussault et al. 2003). PXR, CAR (constitutive androgen receptor) and VDR induce CYP3A4 to convert CDCA to hyocholic acid and LCA to hyodeoxycholic acid in the liver and intestine. These soluble, non-toxic bile acids are conjugated by UDPglucuronosyl transferase (UGT2B4) and excreted into bile or urine. PXR also induces drug transporters, MDR1, MRP3 and OATP2. Thus PXR coordinately regulate genes involved in bile acid synthesis, transport, and detoxification, thus protecting the liver and intestine from accumulating toxic bile acids. CYP3A4 is the most abundant P450 isozyme in human liver and intestine and metabolizes about 60% of prescription drugs, many of them are known to activate PXR. A potent PXR agonist, rifampicin has been used to treat pruritis in patients with intrahepatic cholestasis and primary biliary cirrhosis (Hofmann 2002; Prince et al. 2002). Selective PXR agonists with low hepatotoxicity may be developed for treating cholestatic pruritis.

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