Ursodeoxycholic acid prevents hepatic cytochrome P450 isozyme reduction in rats with deoxycholic acid-induced liver injury.
OBJECTIVE
Hydrophobic bile acids, such as deoxycholic acid produce cholestatic liver injury. Ursodeoxycholic acid has been shown to be useful in the treatment of cholestatic liver disease.


METHODS
In this study, we investigated the effects of deoxycholic acid or ursodeoxycholic acid (1% of diet, for 14 days) and their combination (1% each) on expression of hepatic cytochrome P450 isozymes, their related enzyme activities and mRNA level in rats.


RESULTS
Adding 1% deoxycholic acid to chow caused a marked increase in serum total bilirubin (47-fold) and total bile acid (8-fold) concentrations and in alkaline phosphatase (2.5-fold, p<0.01) and alanine aminotransferase activities (23.5-fold, p<0.01). Adding the same dose of ursodeoxycholic acid along with the deoxycholic acid mitigated both the rise in serum total bilirubin and bile acid concentrations and that in alkaline phosphatase and alanine aminotransferase activities, although the use of ursodeoxycholic acid alone did not affect any of the above. Feeding 1% deoxycholic acid caused a decrease (48% of control) in total cytochrome P450 content in hepatic microsomes. Addition of 1% ursodeoxycholic acid along with the 1% deoxycholic acid completely prevented the decrease in total cytochrome P450 content. Feeding ursodeoxycholic acid alone did not affect the total cytochrome P450 content. The expression of cytochrome P450 2B1, 2E1, 3A2, 2C6, 2C11 and 4A1 proteins in hepatic microsomes was decreased by deoxycholic acid (44, 51, 23, 59, 30 and 74% of control, respectively). Likewise, the activities of cytochrome P450 2B1 (pentoxyresorufin O-depentylation), 2E1 (aniline p-hydroxylation) and 3A2 (testosterone 6beta-hydroxylation) isozymes and the 3A2 mRNA levels in liver were decreased by deoxycholic acid. Addition of 1% ursodeoxycholic acid to 1% deoxycholic acid also prevented the decrease in these cytochrome P450 proteins, related enzyme activities and mRNA levels in liver.


CONCLUSIONS
These results indicate that, in rats with deoxycholic acid-induced liver injury, ursodeoxycholic acid prevents the decrease in hepatic cytochrome P450 isozymes and suggest that ursodeoxycholic acid is useful for the treatment of liver injury in terms of aiding the normalization of the hepatic drug-metabolizing system.
Tanaka
M
M
Department of Pharmacology, St. Marianna University School of Medicine, Kawasaki, Japan.
Nakura
H
H
Tateishi
T
T
Watanabe
M
M
Nakaya
S
S
Kumai
T
T
Kobayashi
S
S
D000818:Animals; D002756:Cholagogues and Choleretics / Q000494:pharmacology* / Q000627:therapeutic use; D002779:Cholestasis / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D003840:Deoxycholic Acid / Q000633:toxicity; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008297:Male; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014580:Ursodeoxycholic Acid / Q000494:pharmacology* / Q000627:therapeutic use
D002756:Cholagogues and Choleretics; D012333:RNA, Messenger; D003840:Deoxycholic Acid; D014580:Ursodeoxycholic Acid; D003577:Cytochrome P-450 Enzyme System