RT Journal Article
SR Electronic
T1 A Novel Mechanism for Polychlorinated Biphenyl-Induced Decrease in Serum Thyroxine Level in Rats
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1949
OP 1955
DO 10.1124/dmd.107.017327
VO 35
IS 10
A1 Yoshihisa Kato
A1 Shin-ichi Ikushiro
A1 Rie Takiguchi
A1 Koichi Haraguchi
A1 Nobuyuki Koga
A1 Shinya Uchida
A1 Toshiyuki Sakaki
A1 Shizuo Yamada
A1 Jun Kanno
A1 Masakuni Degawa
YR 2007
UL http://dmd.aspetjournals.org/content/35/10/1949.abstract
AB We have previously suggested that the decrease in the levels of serum total thyroxine (T4) and free T4 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 T4-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 T4 and further investigated an exact mechanism for the KC500-induced decrease in the T4. At 4 days after final treatment with KC500, the serum total T4 and free T4 levels were markedly decreased in both Wistar and UGT1A-deficient Wistar (Gunn) rats, whereas significant increases in hepatic T4-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 [125I]T4 administered to the KC500-pretreated Wistar and Gunn rats was faster than that to the corresponding control (KC500-untreated) rats. The accumulated level of [125I]T4 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 T4 in both Wistar and Gunn rats and further indicated that the KC500-induced decrease would occur through increase in accumulation of T4 in several tissues, especially the liver, rather than increase in hepatic T4-UDP-GT activity. The American Society for Pharmacology and Experimental Therapeutics