Ursodeoxycholic acid (UDCA) prevents DCA effects on male mouse liver via up-regulation of CYP [correction of CXP] and preservation of BSEP activities.
To investigate whether ursodeoxycholic acid (UDCA) can prevent metabolic impairment induced by deoxycholic acid (DCA), we evaluated the effects of these bile acids on murine CYP enzymes and the relationship with canalicular bile salt export pump (Bsep) expression. In Swiss Albino CD1 mice, UDCA and DCA were injected intraperitoneally either singly, concurrently, or sequentially (UDCA 1 hour before DCA) at equimolar 24.4 mg/kg body weight (BW) doses. CYP content, NADPH-CYP-c-reductase, and individual mixed function oxidases (MFO) were measured 24 hours later. Modulations were observed mainly in males: whereas DCA decreased MFO activities to various isoenzymes with respect to controls (up to 43%, CYP1A2-linked activity), UDCA boosted them (up to 6-fold, testosterone 16 beta-hydroxylase); concurrent administration of UDCA and DCA provided a preventive effect, enhancing MFO activity with respect to single administration of DCA by up to 4.4-fold in the CYP3A1/2 and CYP2B1/2 (6 beta-hydroxylase) and by 2.1-fold in the CYP2E1 (p-nitrophenol hydroxylase). In males (but not females), sequential administration (UDCA then DCA) produced a rather similar protective pattern, but the extent of recovery was generally smaller. Western immunoblotting results for the most affected isoenzymes (CYP3A1/2 and CYP2E1) and Bsep confirmed that UDCA can both prevent and reduce the CYP-dependent MFO inactivation and Bsep down-regulation caused by DCA. These findings may shed further light on the mechanisms responsible for UDCA's protective role in the treatment of cholestatic liver disease.
Paolini
Moreno
M
Department of Pharmacology, University of Bologna, Bologna, Italy.
Pozzetti
Laura
L
Montagnani
Marco
M
Potenza
Giuseppa
G
Sabatini
Laura
L
Antelli
Alessandra
A
Cantelli-Forti
Giorgio
G
Roda
Aldo
A
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003840:Deoxycholic Acid / Q000494:pharmacology*; D003902:Detergents / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C490549:Abcb11 protein, mouse; D002756:Cholagogues and Choleretics; D003902:Detergents; D003840:Deoxycholic Acid; D014580:Ursodeoxycholic Acid; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; D019388:Cytochrome P-450 CYP1A2; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; C025619:steroid 16-beta-hydroxylase; C022657:steroid hormone 6-beta-hydroxylase