Document Detail

Bile acid structure and selective modulation of murine hepatic cytochrome P450-linked enzymes.
MedLine Citation:
PMID:  10462380     Owner:  NLM     Status:  MEDLINE    
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 x 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 6beta-hydroxylase, and N-demethylation of aminopyrine) in a dose-dependent fashion was enhanced ( approximately 2-3-fold). CYP2E1- (hydroxylation of p-nitrophenol), CYP1A2-(O-demethylation of methoxyresorufin), CYP2A1/2- and CYP2B1/2-(6alpha-hydroxylase), and CYP2B9- (16alpha-hydroxylase) dependent MFOs, as well as 7alpha-, 16beta-, 2alpha-, and 2beta-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.
M Paolini; L Pozzetti; F Piazza; G Cantelli-Forti; A Roda
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Hepatology (Baltimore, Md.)     Volume:  30     ISSN:  0270-9139     ISO Abbreviation:  Hepatology     Publication Date:  1999 Sep 
Date Detail:
Created Date:  1999-09-16     Completed Date:  1999-09-16     Revised Date:  2004-03-30    
Medline Journal Info:
Nlm Unique ID:  8302946     Medline TA:  Hepatology     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  730-9     Citation Subset:  IM    
Department of Pharmacology, University of Bologna, Bologna, Italy.
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MeSH Terms
Aryl Hydrocarbon Hydroxylases*
Bile Acids and Salts / pharmacology*
Cytochrome P-450 Enzyme System / metabolism*
Enzyme Induction / drug effects
Liver / drug effects*,  enzymology
Steroid 16-alpha-Hydroxylase
Taurodeoxycholic Acid / analogs & derivatives,  pharmacology
Ursodeoxycholic Acid / pharmacology
Reg. No./Substance:
0/Bile Acids and Salts; 128-13-2/Ursodeoxycholic Acid; 2958-04-5/taurohyodeoxycholic acid; 516-50-7/Taurodeoxycholic Acid; 9035-51-2/Cytochrome P-450 Enzyme System; EC Hydrocarbon Hydroxylases; EC protein, rat; EC 16-alpha-Hydroxylase

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