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Ursodeoxycholic acid (UDCA) prevents DCA effects on male mouse liver via up‐regulation of CXP and preservation of BSEP activities
Author(s) -
Paolini Moreno,
Pozzetti Laura,
Montagnani Marco,
Potenza Giuseppa,
Sabatini Laura,
Antelli Alessandra,
CantelliForti Giorgio,
Roda Aldo
Publication year - 2002
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2002.34939
Subject(s) - ursodeoxycholic acid , cyp2e1 , medicine , endocrinology , bile acid , deoxycholic acid , chemistry , reductase , pharmacology , isozyme , cytochrome p450 , enzyme , metabolism , biochemistry
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 16β‐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 (6β‐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.