Bile acid structure and selective modulation of murine hepatic cytochrome P450-linked enzymes

We examined the effects of the administration of different bile acids on in vivo hepatic murine cytochrome P450 (CYP) content, nicotinamide adenine di nucleotide phosphate (NADPH)-CYP-reductase, and individual mixed-function o xidases (MFOs). Neither CYP level nor reductase were appreciably affected b y single intraperitoneal administration of taurodeoxycholic acid (TDCA) (12 .2 or 24.4 mg x kg(-1) bw). MFO to various isoenzymes were slightly reduced 24 hours after treatment. Taurohyodeoxycholic acid (THDCA) and tauroursode oxycholic acid (TUDCA) both induced CYP, reductase, and MFOs. CYP3A1/2-link ed activity (i.e., testosterone 6 beta-hydroxylase, and N-demethylation of aminopyrine) in a dose-dependent fashion was enhanced (similar to 2-3-fold) . CYP2E1- (hydroxylation of p-nitrophenol), CYP1A2-(O-demethylation of meth oxyresorufin), CYP2A1/2- and CYP2B1/2-(6 alpha-hydroxylase), and CYP2B9- (1 6 alpha-hydroxylase) dependent MFOs, as well as 7 alpha-, 16 beta-, 2 alpha -, and 2 beta-hydroxylations, were all significantly induced by THDCA, Apar t from alkoxyresorufin metabolism and a modest CYP2E1 increase, TUDCA behav ed like THDCA. A generalized induction was also recorded after ursodeoxycho lic acid (UDCA) administration. THDCA and TDCA did not show substantial dif ferences in the N-demethylation of aminopyrine when different species (rat vs. mouse) and administration route (intraperitoneal vs. intravenous) were compared. Results on the most affected isoenzymes, CYP3A1/2 (THDCA, TUDCA, and UDCA) and CYP2EI (UDCA), were sustained by means of Western immunoblott ing. CYP3A induction was paralleled by a corresponding increase in mRNA. Th ese data could partially explain the therapeutic mechanism of UDCA, TUDCA, and THDCA in chronic cholestatic liver disease. CYP3A induction, which is l inked to P-glycoprotein (Pgp) family overexpression, may enhance hepatic me tabolism, transport, and excretion of toxic endogenous lipophilic bile acid s.