A possible mechanism for decrease in serum thyroxine level by polychlorinated biphenyls

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In the present study, we determined whether or not a consecutive treatment with Kanechlor-500 (KC500) at a relatively low dose (10 mg/kg, i.p., once daily for 10 days) results in decrease in the level of serum total thyroxine (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, while significant increases in hepatic T_4-UDP-glucuronosyltransferase (T_4-UDP-GT) activity were observed in Wistar rats but not in Gunn rats. 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 … More the KC500-pretreated rats. The present findings demonstrated that a consecutive treatment with KC500 resulted in significant decrease in 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.To clarify the UGT isoform(s) responsible for the glucuronidation of thyroid hormone T_4 in the human liver, the T_4-glucuronidation activities of recombinant human UGT isoforms and 7 individual human liver microsomes were comparatively examined. The findings strongly indicated that glucuronidation of T_4 in the human liver was mediated by UGT1A subfamily enzymes, especially UGT1A1 and UGT1A3, and further suggested that the interindividual difference would come from that in the expression levels of UGT1A1 and UGT1A3 in individual human livers. Further studies are necessary for understanding the susceptibility toward a PCB-mediated decrease in serum T_4 level in animals including humans. Less