Mechanism for the prevention of cholestasis involving cytochrome P4503A overexpression.
BACKGROUND
To clarify the preventive effect of taurohyodeoxycholic acid on liver cholestasis induced by toxic bile acids in rats, we evaluated whether modulation of cytochrome P4503A-linked oxidases is involved in the hepatic bile acid retention and secretion mechanism. We investigated whether the safe or the toxic taurochenodeoxycholic acid, administered singly or together, affects cytochrome P450-catalyzed drug metabolism or biliary parameters. We also considered whether the inhibition of the P-glycoprotein export pump by vinblastine might be related to cytochrome P4503A overexpression.


METHODS
Hydroxylation of testosterone and N-demethylation of aminopyrine were studied in subcellular rat liver preparations after intravenous infusion of hepatoprotective and toxic bile acids administered singly or together. Bile flow, calcium secretion, biliary enzymes activity, and secretion rates of the endogenous and administrated bile acids were determined. CYP3A-dependent monooxygenases were also measured in the same coinfusion model in the presence of vinblastine.


RESULTS
Although wide modulation of the activities of different P450 subfamily of isoenzymes was seen, P4503A-associated monooxygenases showed similar patterns in the various situations, i.e., induction by taurohyodeoxycholic acid, reduction by taurochenodeoxycholic acid, and protection (intermediate induction) in the coinfusion experiments. This correlates well with biliary parameters demonstrating the hepatoprotective ability of taurohyodeoxycholic acid. Coadministration of bile acids and vinblastine significantly modifies CYP3A-linked activities.


CONCLUSIONS
Bile acid structure seems to be linked with hepatotoxicity/hepatoprotection and P4503A modulation. Taurohyodeoxycholic acid could be therapeutic in cholestatic liver disease by inducing P4503A; we can hypothesize that an associated P-glycoprotein expression might facilitate biliary excretion of toxic taurochenodeoxycholic acid accumulated in the liver during cholestasis.
Paolini
M
M
Department of Pharmacology, University of Bologna, Italy.
Pozzetti
L
L
Piazza
F
F
Guerra
M C
MC
Speroni
E
E
Cantelli-Forti
G
G
Roda
A
A
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001646:Bile / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002780:Cholestasis, Intrahepatic / Q000139:chemically induced / Q000517:prevention & control*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013655:Taurochenodeoxycholic Acid / Q000633:toxicity; D013657:Taurodeoxycholic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D014747:Vinblastine / Q000494:pharmacology
C083510:taurohyodeoxycholic acid; D013655:Taurochenodeoxycholic Acid; D013657:Taurodeoxycholic Acid; D014747:Vinblastine; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D002118:Calcium