Troglitazone-induced intrahepatic cholestasis by an interference with the hepatobiliary export of bile acids in male and female rats. Correlation with the gender difference in troglitazone sulfate formation and the inhibition of the canalicular bile salt export pump (Bsep) by troglitazone and troglitazone sulfate
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Abstract
Troglitazone is a thiazolidinedione insulin sensitizer drug for the treatment of type
2 non-insulin-dependent diabetes mellitus (NIDDM). Based on an increasing number of
reports on troglitazone-associated liver toxicity, the cholestatic potential of troglitazone
and its major metabolite troglitazone sulfate has been investigated. In isolated perfused
rat livers troglitazone (10 microM) reduced the bile flow by 25% (female) to 50% (male)
within 60 min. After single intravenous administrations of troglitazone to rats of
both genders, rapid and dose-dependent increases in the plasma bile acid concentrations
were observed, with male rats being more sensitive than female rats. In male rat liver
tissue fivefold higher troglitazone sulfate levels were measured as compared to female
rat liver tissue. This difference was due to the formation rate of troglitazone sulfate,
which was four times faster in cytosolic fractions of male rat liver as compared to
female rat liver (Clint=132 and 35 microl min(-1) mg(-1), respectively). Troglitazone
sulfate strongly inhibited the ATP-dependent taurocholate transport mediated by the
canalicular bile salt export pump (Bsep) in isolated canalicular rat liver plasma
membrane preparations of both genders (IC(50) value of 0.4-0.6 microM), while troglitazone
was 10 times less potent (IC(50) values of 3.9 microM). This high Bsep inhibition
potential and the efficient formation and accumulation of troglitazone sulfate in
liver tissue, suggested that troglitazone sulfate was mainly responsible for the interaction
with the hepatobiliary export of bile acids at the level of the canalicular Bsep in
rats. Such an interaction might lead potentially also in man to a troglitazone-induced
intrahepatic cholestasis, potentially contributing to the formation of troglitazone-induced
liver injuries.