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.
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.
Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Sanuki, Kagawa, Japan. kato@kph.bunri-u.ac.jp
Yoshihisa
Y
Kato
Koichi
K
Haraguchi
Makiko
M
Kubota
Yoshiki
Y
Seto
Takashi
T
Okura
Shin-ichi
S
Ikushiro
Nobuyuki
N
Koga
Shizuo
S
Yamada
Masakuni
M
Degawa
D000818:Animals; D001646:Bile / Q000737:chemistry; D001798:Blood Proteins / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D004965:Estrogen Antagonists / Q000494:pharmacology; D020723:Glucuronic Acid / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D000072317:Polychlorinated Dibenzodioxins / Q000031:analogs & derivatives*; D011485:Protein Binding / Q000187:drug effects; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics; D014018:Tissue Distribution / Q000187:drug effects
D001798:Blood Proteins; D004965:Estrogen Antagonists; D007527:Isoenzymes; D000072317:Polychlorinated Dibenzodioxins; D020723:Glucuronic Acid; D013972:Thyrotropin; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D014453:Glucuronosyltransferase; D013974:Thyroxine; C023035:3,4,5,3',4'-pentachlorobiphenyl