PT - JOURNAL ARTICLE AU - Kato, Yoshihisa AU - Haraguchi, Koichi AU - Kubota, Makiko AU - Seto, Yoshiki AU - Okura, Takashi AU - Ikushiro, Shin-ichi AU - Koga, Nobuyuki AU - Yamada, Shizuo AU - Degawa, Masakuni TI - A Possible Mechanism for the Decrease in Serum Thyroxine Level by a TCDD-Like PCB Congener, 3,3',4,4',5-Pentachlorobiphenyl in Mice AID - 10.1124/dmd.109.029348 DP - 2009 Jan 01 TA - Drug Metabolism and Disposition PG - dmd.109.029348 4099 - http://dmd.aspetjournals.org/content/early/2009/09/28/dmd.109.029348.short 4100 - http://dmd.aspetjournals.org/content/early/2009/09/28/dmd.109.029348.full AB - Serum total thyroxine (T4) and free T4 levels were markedly decreased 7 days after treatment with 3,3',4,4',5-pentachlorobiphenyl (CB126) (2.5 mg/kg, intraperitoneal) in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-sensitive C57BL/6 mice but not in TCDD-resistant DBA/2 mice. At the same time, the level and activity of hepatic T4-UDP-glucuronosyltransferase (T4-UGT) were significantly increased in C57BL/6 mice but not in DBA/2 mice. Furthermore, the amounts of biliary [125I]T4 and [125I]T4-glucuronide after injection of [125I]T4 were increased by CB126-pretretment in C57BL/6 mice, but not in DBA/2 mice. Clearance of [125I]T4 from serum was also promoted by CB126-pretreatment in C57BL/6 mice, but not in DBA/2 mice. On the other hand, no significant changes in the steady-state volumes of distribution of [125I]T4 and in the concentration ratio (Kp value) of the liver to serum by CB126-pretreatment were observed in either strain of mice. Because liver weight was increased by CB126-pretreatment in C57BL/6 mice, but not in DBA/2 mice, hepatic total [125I]T4 was increased only in C57BL/6 mice. The present findings indicate that CB126-mediated decrease in serum T4 occurs through the increase in hepatic T4-UGT and the enhanced accumulation of hepatic T4 along with development of liver hypertrophy.The American Society for Pharmacology and Experimental Therapeutics