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 T-4 by Kanechor 500 (KC500) in rats would occur through the increase in hepatic T-4 accumulation rather than the increase in hepatic T-4-glucuronyl transferase activity. In the present study, to understand the mechanism underlying the KC500-mediated increase in hepatic T-4 accumulation, we examined the relationship between the KC500-mediated changes in hepatic T-4 accumulation and the expression levels of mRNAs of hepatic transporters including T-4 transporters. [I-5(12)]T-4 was intravenously injected into KC500-pretreated and control (KC500-untreated) Wistar rats, and [I-5(12)]T-4 uptake levels of liver parenchymal cells were comparatively examined. The amount of [I-5(12)]T-4 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 T-4 influx transporter LAT1 was observed up to 96 hr later, while a significant increase in hepatic T-4 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 T-4 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 T-4 accumulation occurs, at least in part, through the increase in the expression of hepatic T-4-transporters, such as LAT1 and Oatp2.