Organic anion transporter 1B1: An important factor in hepatic thyroid hormone and estrogen transport and metabolism

Sulfation is an important pathway in the metabolism of thyroid hormone and estrogens. Sulfation of estrogens is reversible by estrogen sulfatase, but sulfation of thyroid hormone accelerates its degradation by the type 1 deiodinase in liver. Organic anion transporters (OATPs) are capable of transporting iodothyronine sulfates such as T(4) sulfate (T(4)S), T(3)S, and rT(3)S or estrogen sulfates like estrone sulfate (E1S), but the major hepatic transporter for these conjugates has not been identified. A possible candidate is OATP1B1 because model substrates for this transporter include the bilirubin mimic bromosulfophthalein (BSP) and E1S, and it is highly and specifically expressed in liver. Therefore, OATP1B1-transfected COS1 cells were studied by analysis of BSP, E1S, and iodothyronine sulfate uptake and metabolism. Two Caucasian populations (155 blood donors and 1012 participants of the Rotterdam Scan Study) were genotyped for the OATP1B1-Val174Ala polymorphism and associated with bilirubin, E1S, and T(4)S levels. OATP1B1-transfected cells strongly induced uptake of BSP, E1S, T(4)S, T(3)S, and rT(3)S compared with mock-transfected cells. Metabolism of iodothyronine sulfates by co-transfected type 1 deiodinase was greatly augmented in the presence of OATP1B1. OATP1B1-Val(174) showed a 40% higher induction of transport and metabolism of these substrates than OATP1B1-Ala(174). Carriers of the OATP1B1-Ala(174) allele had higher serum bilirubin, E1S, and T(4)S levels. In conclusion, OATP1B1 is an important factor in hepatic transport and metabolism of bilirubin, E1S, and iodothyronine sulfates. OATP1B1-Ala(174) displays decreased transport activity and thereby gives rise to higher bilirubin, E1S, and T(4)S levels in carriers of this polymorphism.