Bile acid structure and selective modulation of murine... : Hepatology (original) (raw)

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

Paolini, Moreno1; Pozzetti, Laura1; Piazza, Francesco2; Cantelli-Forti, Giorgio1; Roda, Aldo*,2

1Departments of Pharmacology, University of Bologna, Bologna, Italy

2Pharmaceutical Sciences, University of Bologna, Bologna, Italy

*Address reprint requests to: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Bologna, Via Belmeloro, 6, 40126, Bologna, Italy. fax: 39-051-343398

Received May 26, 1998; accepted June 29, 1999; previously published online December 30, 2003

Abstract

We examined the effects of the administration of different bile acids on in vivo hepatic murine cytochrome P450 (CYP) content, nicotinamide adenine dinucleotide phosphate (NADPH)-CYP-reductase, and individual mixed-function oxidases (MFOs). Neither CYP level nor reductase were appreciably affected by single intraperitoneal administration of taurodeoxycholic acid (TDCA) (12.2 or 24.4 mg × kg−1 bw). MFO to various isoenzymes were slightly reduced 24 hours after treatment. Taurohyodeoxycholic acid (THDCA) and tauroursodeoxycholic acid (TUDCA) both induced CYP, reductase, and MFOs. CYP3A1/2-linked activity (i.e., testosterone 6β-hydroxylase, and _N_-demethylation of aminopyrine) in a dose-dependent fashion was enhanced (˜2-3-fold). CYP2E1- (hydroxylation of _p_-nitrophenol), CYP1A2-(_O_-demethylation of methoxyresorufin), CYP2A1/2- and CYP2B1/2-(6α-hydroxylase), and CYP2B9- (16α-hydroxylase) dependent MFOs, as well as 7α-, 16β-, 2α-, and 2β-hydroxylations, were all significantly induced by THDCA. Apart from alkoxyresorufin metabolism and a modest CYP2E1 increase, TUDCA behaved like THDCA. A generalized induction was also recorded after ursodeoxycholic acid (UDCA) administration. THDCA and TDCA did not show substantial differences 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 CYP2E1 (UDCA), were sustained by means of Western immunoblotting. CYP3A induction was paralleled by a corresponding increase in mRNA. These data could partially explain the therapeutic mechanism of UDCA, TUDCA, and THDCA in chronic cholestatic liver disease. CYP3A induction, which is linked to P-glycoprotein (Pgp) family overexpression, may enhance hepatic metabolism, transport, and excretion of toxic endogenous lipophilic bile acids.