title: Hepatobiliary disposition of thyroid hormone in Mrp2-deficient TR- rats: reduced biliary excretion of thyroxine glucuronide does not prevent xenobiotic-induced hypothyroidism.
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.
authors.affiliation: Discovery Toxicology, Bristol Myers Squibb Company, Princeton, New Jersey 08543, USA. Iloyd.lecureux@bms.com
authors.forename: Lloyd
authors.initials: L
authors.lastname: Lecureux
authors.forename: Matthew Z
authors.initials: MZ
authors.lastname: Dieter
authors.forename: David M
authors.initials: DM
authors.lastname: Nelson
authors.forename: Linda
authors.initials: L
authors.lastname: Watson
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
authors.forename: Brian
authors.initials: B
authors.lastname: Gemzik
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Klaassen
authors.forename: Lois D
authors.initials: LD
authors.lastname: Lehman-McKeeman
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D001646:Bile / Q000378:metabolism*; D001659:Biliary Tract / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D020719:Glucuronides / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D007037:Hypothyroidism / Q000139:chemically induced* / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D013961:Thyroid Gland / Q000378:metabolism / Q000473:pathology; D013963:Thyroid Hormones / Q000378:metabolism*; D013972:Thyrotropin / Q000378:metabolism; D013974:Thyroxine / Q000378:metabolism*; D014284:Triiodothyronine / Q000378:metabolism; D015262:Xenobiotics / Q000633:toxicity*
chemical_list: D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D020719:Glucuronides; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; D015262:Xenobiotics; D014284:Triiodothyronine; D013972:Thyrotropin; D013974:Thyroxine