ToxSci Advance Access published online on February 11, 2009
Toxicological Sciences, 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
1 Discovery Toxicology, Bristol Myers Squibb Company, Princeton, NJ 08543 2 Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66103
Received October 20, 2008; revision received January 30, 2009; 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 (UDP-GT), 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 (TSH) levels 2-fold. 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 (Cl bile) was approximately 0.85 and 0.2 ml/hr 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.
* Present address: Abbott Laboratories, 100 Abbott Park Road, R468 Ap13A, Abbott Park, IL 60064
# Present address: Beatson Institute for Cancer Research, University of Glasgow, Glasgow, Scotland
Present address: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080