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. [¹²⁵I]T₄ was intravenously injected into KC500-pretreated and control (KC500-untreated) Wistar rats, and [¹²⁵I]T₄ uptake levels of liver parenchymal cells were comparatively examined. The amount of [¹²⁵I]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.