title: In vitro metabolism of thyroxine by rat and human hepatocytes.
abstract: 1. The liver metabolizes thyroxine (T(4)) through two major pathways: deiodination and conjugation. Following exposure to xenobiotics, T(4) conjugation increases through the induction of hepatic uridine diphosphate glucuronosyltransferase (UGT) in rodents; however, it is uncertain to what degree different species employ deiodination and conjugation in the metabolism of T(4). The objective of this study was to compare the metabolism of T4 in untreated and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153)-treated primary sandwich-cultured hepatocytes from rat (SCRH) and human (SCHH). 2. Basal metabolite concentrations were 13 times higher in the medium of SCRH compared to SCHH. Metabolite distribution in the medium of SCRH versus SCHH was as follows: T(4)G, (91.6 versus 5.3%); T4S, (3.6 versus 4.4%) and T(3) + rT(3), (4.9 versus 90.3%). PCB 153 induced T(4)G in the medium of SCRH and SCHH; however, T(4)S and T(3) + rT(3) were changed but to a much lesser degree. 3. The results indicate that baseline T(4) glucuronidation is greater in SCRH compared to SCHH. These data also suggest that glucuronidation may be a more important pathway for T(4) metabolism in rats and deiodination may be a favored pathway in humans; however, with PCB 153 treatment these data support glucuronidation as a primary route of T(4) metabolism in both rat and humans.
authors.affiliation: Pharmacokinetics Branch, Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency , Research Triangle Park, NC , USA .
authors.forename: Vicki M
authors.initials: VM
authors.lastname: Richardson
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Ferguson
authors.forename: Yusupha M
authors.initials: YM
authors.lastname: Sey
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Devito
mesh_terms: D000368:Aged; D000818:Animals; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D011078:Polychlorinated Biphenyls / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013974:Thyroxine / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D013997:Time Factors; D055815:Young Adult
chemical_list: D011078:Polychlorinated Biphenyls; D013974:Thyroxine; C014024:2,4,5,2',4',5'-hexachlorobiphenyl