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ToxSci Advance Access published online on October 27, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfi020
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received July 28, 2004
Accepted October 17, 2004

Biotransformation and Toxicokinetics

Xenobiotics Inhibit Hepatic Uptake and Biliary Excretion of Taurocholate in Rat Hepatocytes

Daniel C. Kemp 1, Maciej J. Zamek-Gliszczynski 2, and Kim L. R. Brouwer 3*

1 Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC 27599
2 School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599
3 Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC 27599; School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599

* To whom correspondence should be addressed.
Kim L. R. Brouwer, E-mail: kbrouwer{at}unc.edu


  Abstract

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 µM) decreased the initial rate of taurocholate uptake ~3-fold; the initial uptake rate of estradiol-17{beta}-D-glucuronide, a substrate of the organic anion transporting polypeptides, also was decreased ~4-fold. Bosentan (100 µM) decreased the initial uptake rate of taurocholate and estradiol-17{beta}-D-glucuronide by ~12- and ~7-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 µM troglitazone (27 ± 2%) and 100 µM bosentan (10 ± 6%). In conclusion, xenobiotics may alter hepatic bile acid transport by inhibiting both hepatic uptake and biliary excretion.

Keywords: Hepatotoxicity; Taurocholate; Troglitazone; Bosentan; Hepatocytes; Hepatobiliary Transport.
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