Hepatobiliary disposition of thyroid hormone in Mrp2-deficient TR- rats: reduced biliary excretion of thyroxine glucuronide does not prevent xenobiotic-induced hypothyroidism.
Toxicol Sci
; 108(2): 482-91, 2009 Apr.
Article
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| MEDLINE
| ID: mdl-19211616
ABSTRACT
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 [(125)I]T4 to rats dosed with PB and DMP 904 (4 days). PB and DMP 904 increased plasma clearance and hepatic uptake of [(125)I]T4 equivalents in Wistar but not TR(-) rats. Total biliary clearance (Cl(bile)) 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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Hormonas Tiroideas
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Tiroxina
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Bilis
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Sistema Biliar
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Receptores de Hormona Tiroidea
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Xenobióticos
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Transportadoras de Casetes de Unión a ATP
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Hipotiroidismo
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Hígado
Límite:
Animals
Idioma:
En
Revista:
Toxicol Sci
Asunto de la revista:
TOXICOLOGIA
Año:
2009
Tipo del documento:
Article
País de afiliación:
Estados Unidos