Possible mechanism for the polychlorinated bipheny-linduced liver-selective accumulation of thyroxine in rats.

We have previously reported that decrease in level of serum thyroxine T4 by Kanechor 500 (KC500) in rats would occur through the increase in hepatic T4 accumulation rather than the increase in hepatic T4 -glucuronyl transferase activity. In the present study, to understand the mechanism underlying the KC500-mediated increase in hepatic T4 accumulation, we examined the relationship between the KC500-mediated changes in hepatic T4 accumulation and the expression levels of mRNAs of hepatic transporters including T4 transporters. [125 I]T4 was intravenously injected into KC500-pretreated and control (KC500-untreated) Wistar rats, and [125 I]T4 uptake levels of liver parenchymal cells were comparatively examined. The amount of [125 I]T4 uptake by hepatic cells increased in a time-dependent manner up to 96 hr after KC500 treatment. Following KC500 treatment, a time-dependent increase in the mRNA level of hepatic T4 influx transporter LAT1 was observed up to 96 hr later, while a significant increase in hepatic T4 influx transporter Oatp2 mRNA occurred only at 96 hr later. No KC500-mediated increases in the mRNAs of other hepatic transporters (Oatp1, Oatp3, Oatp4, Ntcp, LAT2, and Mrp2) were observed at any timepoints, although the mRNA expression of the T4 conjugate(s) efflux transporter Mrp3 significantly increased in a time-dependent manner 24-96 hr following KC500 treatment. The present findings suggest that KC500-mediated increase in hepatic T4 accumulation occurs, at least in part, through the increase in the expression of hepatic T4 -transporters, such as LAT1 and Oatp2.