A Possible Mechanism for the Decrease in Serum Thyroxine Level by a 2,3,7,8-Tetrachlorodibenzo-p-dioxin-Like Polychlorinated Biphenyl Congener, 3,3 ',4,4 ',5-Pentachlorobiphenyl in Mice
Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Sanuki, Kagawa, Japan.Drug metabolism and disposition: the biological fate of chemicals (Impact Factor: 3.25). 09/2009; 38(1):150-6. DOI: 10.1124/dmd.109.029348
Serum total thyroxine (T(4)) and free T(4) levels were markedly decreased 7 days after treatment with 3,3',4,4',5-pentachlorobiphenyl (CB126) (2.5 mg/kg i.p.) 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 T(4)-UDP-glucuronosyltransferase (T(4)-UGT) were significantly increased in C57BL/6 mice but not in DBA/2 mice. Furthermore, the amounts of biliary [(125)I]T(4) and [(125)I]T(4) glucuronide after injection of [(125)I]T(4) were increased by CB126 pretreatment in C57BL/6 mice but not in DBA/2 mice. Clearance of [(125)I]T(4) 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 [(125)I]T(4) and in the concentration ratio (K(p) 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 [(125)I]T(4) was increased only in C57BL/6 mice. The present findings indicate that CB126-mediated decrease in serum T(4) occurs through the increase in hepatic T(4)-UGT and the enhanced accumulation of hepatic T(4) along with development of liver hypertrophy.
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- "In addition, PentaCBtreatment led to no significant change in the level of serum TSH, one of the factors regulating the level of serum total T 4 (Capen 1997; McClain 1989; Saito et al., 1991 ), in either strain of mice. These results are identified with those in previous reports concerning the effects of PCB on the level of serum TSH in rats and mice (Hallgren et al., 2001; Hood et al., 1999; Kato et al., 2004 Kato et al., , 2007 Kato et al., , 2010a Liu et al., 1995). In conclusion, the present findings indicate that PentaCB-mediated decrease in serum T 4 level in mice is mainly dependent on the increase in hepatic accumulation (promotion of the transportation from serum to liver and/or inhibition of the efflux from hepatic cells) of T 4 and strongly suggest that in WT mice, PentaCB-mediated decrease in serum T 4 occurs, at least in part, through the inhibition of a T 4 –TTR complex formation by the hydroxylated metabolites of PentaCB. "
ABSTRACT: The relationships between the changes in the levels of serum total thyroxine (T(4)), serum T(4)-transthyretin (TTR) complex, and accumulation of T(4) in tissues by 2,2',4,5,5'-pentachlorobiphenyl (PentaCB) were examined using wild-type C57BL/6 (WT) and its TTR-deficient (TTR-null) mice. The constitutive level of serum total T(4) was much higher in WT mice than in TTR-null mice. In WT mice 4 days after a single intraperitoneal injection with PentaCB (112 mg/kg), serum total T(4) level was significantly decreased along with a decrease in serum T(4)-TTR complex, and the levels of serum total T(4) in the PentaCB-treated WT mice were almost the same to those in PentaCB-untreated (control) TTR-null mice. In addition, a slight decrease in serum total T(4) by PentaCB treatment was observed in TTR-null mice. Furthermore, clearance of [(125)I]T(4) from the serum after [(125)I]T(4)-administration was promoted by the PentaCB-pretreatment in either strain of mice, especially WT mice. On the other hand, accumulation level of [(125)I]T(4) in the liver, but not in extrahepatic tissues, was strikingly enhanced in the PentaCB-pretreated WT and TTR-null mice. Furthermore, in both strains of mice, PentaCB-pretreatment led to significant increases in the steady-state distribution volume of [(125)I]T(4) and the concentration ratio of the liver to serum. The present findings demonstrate that PentaCB-mediated decrease in serum T(4) level occurs mainly through increase in accumulation level of T(4) in the liver and further indicate that the increased accumulation of T(4) in the liver of WT mice is primarily dependent on the PentaCB-mediated inhibition of serum T(4)-TTR complex formation.
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- "j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y t a a p serum TTR rather than do the parent PCB (Brouwer et al., 1998; Lans et al., 1993; Ucán-Marín et al., 2009). However, we have demonstrated that a commercial PCB mixture, the Kanechlor-500 (KC500)-mediated decrease occurs through increased accumulation of T 4 in several tissues, especially the liver, rather than an increase in hepatic T 4 –UGT activity (Kato et al., 2007), and further indicated that decrease in serum T 4 level by CB126 occurs not only through the induction of hepatic T 4 –UGT but also through the enhanced accumulation of hepatic T 4 along with development of liver hypertrophy (Kato et al., 2010a). More recently, we have found that phenobarbital (PB)-mediated decreases in the serum T 4 level in mice, hamsters, and rats occur mainly through an increase in the accumulation level of T 4 in the liver (Kato et al., 2010b). "
ABSTRACT: Serum total thyroxine (T₄) level was markedly decreased, without significant increases in the levels of hepatic T₄-UDP-glucuronosyltransferase (T₄-UGT) and serum thyroid-stimulating hormone, 3 days after treatment with 2,2',4,4',5,5'-hexachlorobiphenyl (CB153) (100mg/kg, ip) in both 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-sensitive C57BL/6 and TCDD-resistant DBA/2 mice. Likewise, in either strain of mice, no CB153-mediated changes in the binding levels of [(125)I]T₄ to serum proteins, such as transthyretin, albumin, and thyroxine binding globulin, were observed, while in CB153-pretreated C57BL/6 mice, but not in CB153-pretreated DBA/2 mice, the levels of biliary [(125)I]₄T and [(125)I]T₄-glucuronide at 90-120 min after injection of [(125)I]T₄ slightly increased, as compared with those in the corresponding control mice. Concerning tissue distribution of [(125)I]T₄, liver-selective increases in the [(125)I]T₄ accumulation by CB153-pretreatment were observed in both C57BL/6 and DBA/2 mice, and the hepatic levels of [(125)I]T₄ in the C57BL/6 and DBA/2 mice became more than 44% and 34% of the [(125)I]T₄ dosed, respectively. The present findings indicated that the CB153-mediated decreases in the level of serum total T₄in C57BL/6 and DBA/2 mice occur mainly through an increase in the accumulation of T₄ in the liver.