Journal
TOXICOLOGICAL SCIENCES
Volume 83, Issue 2, Pages 207-214Publisher
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfi020
Keywords
hepatotoxicity; taurocholate; troglitazone; bosentan; hepatocytes; hepatobiliary transport
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Funding
- NCI NIH HHS [R21 CA106101] Funding Source: Medline
- NIEHS NIH HHS [5-T32-ESO7126] Funding Source: Medline
- NIGMS NIH HHS [GM531674, R01 GM41935, R01 GM041935] Funding Source: Medline
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Reports suggest that troglitazone, and to a lesser extent bosentan, may alter bile acid homeostasis by inhibiting the bile salt export pump. The present studies examined the hypothesis that these xenobiotics may modulate multiple hepatic bile acid transport mechanisms. In suspended rat hepatocytes, troglitazone (10 muM) decreased the initial rate of taurocholate uptake similar to3-fold; the initial uptake rate of estradiol-17beta-D-glucuronide, a substrate of the organic anion transporting polypeptides, also was decreased similar to4-fold. Bosentan (100 muM) decreased the initial uptake rate of taurocholate and estradiol-17beta-D-glucuronide by similar to12- and similar to7-fold, respectively. In sandwich-cultured rat hepatocytes, 10-min accumulation of taurocholate in cells + bile canaliculi (408 +/- 57 pmol/mg protein) was decreased significantly by troglitazone (157 +/- 17 pmol/mg protein, respectively) only in the presence of Na+, the driving force for the sodium taurocholate cotransporting polypeptide. A similar decrease with 10-fold higher concentrations of bosentan was noted. The biliary excretion index of taurocholate (55 +/- 8%) was decreased in the presence of 10 muM troglitazone (27 +/- 2%) and 100 muM bosentan (10 +/- 6%). In conclusion, xenobiotics may alter hepatic bile acid transport by inhibiting both hepatic uptake and biliary excretion.
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