ToxSci Advance Access originally published online on February 11, 2009
Toxicological Sciences 2009 108(2):482-491; doi:10.1093/toxsci/kfp026
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Hepatobiliary Disposition of Thyroid Hormone in Mrp2-Deficient TR– Rats: Reduced Biliary Excretion of Thyroxine Glucuronide Does Not Prevent Xenobiotic-Induced Hypothyroidism
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* Discovery Toxicology, Bristol Myers Squibb Company, Princeton, New Jersey 08543
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66103
4 To whom correspondence should be addressed at Discovery Toxicology, Bristol-Myers Squibb Company, Route 206 and Province Line Road, Princeton, NJ 08543. Fax: (609) 252-7046. E-mail: Iloyd.lecureux{at}bms.com.
Received October 20, 2008; accepted February 3, 2009
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Abstract |
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The hepatobiliary disposition of thyroxine (T4) was evaluated in Groningen Yellow transport deficient (TR–) rats lacking functional multidrug resistance–associated protein 2 (Mrp2; Abcc2). Male Wistar and TR– rats were dosed orally (4 days) with phenobarbital (PB; 100 mg/kg) or DMP 904 (200 mg/kg), after which T4 homeostasis and hepatic cytochromes P450, UDP-glucuronosyltransferase, xenobiotic transporters, and T4 glucuronidation were determined. Serum concentrations of T4 were approximately 50% higher in control TR– rats than Wistars. PB and DMP 904 increased hepatic levels of P450s and T4-glucuronidation (T4-G), and these changes were associated with decreased serum T4 levels in both strains. In Wistar but not TR– rats, DMP 904 increased thyroid stimulating hormone levels twofold. Hepatobiliary clearance of T4 was determined after intravenous infusion of [125I]T4 to rats dosed with PB and DMP 904 (4 days). PB and DMP 904 increased plasma clearance and hepatic uptake of [125I]T4 equivalents in Wistar but not TR– rats. Total biliary clearance (Clbile) was approximately 0.85 and 0.2 ml/h in Wistar and TR– rats, respectively, with virtually no T4-G excreted in bile in TR– rats. Biliary clearance of unconjugated T4 was also lower in control TR– rats than in Wistars, although DMP 904 increased its biliary clearance in both strains. These results suggest that Mrp2 is likely to be responsible for biliary excretion of T4-G and contributes in part to excretion of T4. Decreased biliary clearance of T4 and metabolites in TR– rats mitigated but did not prevent drug-induced changes in serum T4, suggesting that other factors contribute to changes in T4 homeostasis in these rats.
Key Words: thyroxine; TR– rat; Mrp2; hepatic transporters; biliary excretion.
1 Present address: Abbott Laboratories, 100 Abbott Park Road, R468 Ap13A, Abbott Park, IL 60064.
2 Present address: Beatson Institute for Cancer Research, University of Glasgow, Glasgow, UK.
3 Present address: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080.