A novel mechanism for polychlorinated biphenyl-induced decrease in serum thyroxine level in rats.
We have previously suggested that the decrease in the levels of serum total thyroxine (T(4)) and free T(4) by a single administration to rats of Kanechlor-500 (KC500) at a dose of 100 mg/kg is not necessarily dependent on the increase in hepatic T(4)-UDP-glucuronosyltransferase (UDP-GT). In the present study, we determined whether or not a consecutive treatment with KC500 at a relatively low dose (10 mg/kg i.p., once daily for 10 days) results in a decrease in the level of serum total T(4) and further investigated an exact mechanism for the KC500-induced decrease in the T(4). At 4 days after final treatment with KC500, the serum total T(4) and free T(4) levels were markedly decreased in both Wistar and UGT1A-deficient Wistar (Gunn) rats, whereas significant increases in hepatic T(4)-UDP-GT activity were observed in Wistar rats but not in Gunn rats. The level of serum thyroid-stimulating hormone was not significantly changed in either Wistar or Gunn rats. Clearance from serum of the [(125)I]T(4) administered to the KC500-pretreated Wistar and Gunn rats was faster than that to the corresponding control (KC500-untreated) rats. The accumulated level of [(125)I]T(4) was increased in several tissues, especially the liver, in the KC500-pretreated rats. The present findings demonstrated that a consecutive treatment with KC500 resulted in a significant decrease in the level of serum total T(4) in both Wistar and Gunn rats and further indicated that the KC500-induced decrease would occur through increase in accumulation of T(4) in several tissues, especially the liver, rather than increase in hepatic T(4)-UDP-GT activity.
Kato
Yoshihisa
Y
Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Sanuki, Kagawa 769-2193, Japan. kato@kph.bunri-u.ac.jp
Ikushiro
Shin-ichi
S
Takiguchi
Rie
R
Haraguchi
Koichi
K
Koga
Nobuyuki
N
Uchida
Shinya
S
Sakaki
Toshiyuki
T
Yamada
Shizuo
S
Kanno
Jun
J
Degawa
Masakuni
M
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D004785:Environmental Pollutants / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000172:deficiency; D008099:Liver / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013974:Thyroxine / Q000097:blood* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014284:Triiodothyronine / Q000097:blood; D000099148:UGT1A1 Enzyme
D001798:Blood Proteins; D004785:Environmental Pollutants; D014453:Glucuronosyltransferase; D011078:Polychlorinated Biphenyls; D013974:Thyroxine; D014284:Triiodothyronine; C477388:KC 500; C499946:Ugt1a1 protein, rat; D000099148:UGT1A1 Enzyme