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 I deiodinase (D1) in liver. Organic anion transporters are capable of transporting iodothyronine sulfates such as T4 sulfate (T4S), T3 sulfate (T3S) and reverse T3 sulfate (rT3S) or estrogen sulfates like estrone sulfate (E1S), but the major hepatic transporter for these conjugates has not been identified. A possible candidate is OATP1B1 since 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 T4S levels.

OATP1B1-transfected cells strongly induced uptake of BSP, E1S, T4S, T3S and rT3S compared to mock transfected cells. Metabolism of iodothyronine sulfates by co-transfected D1 was greatly augmented in the presence of OATP1B1. OATP1B1-Val¹⁷⁴ showed a 40% higher induction of transport and metabolism of these substrates than OATP1B1-Ala¹⁷⁴. Carriers of the OATP1B1-Ala¹⁷⁴ allele had higher serum bilirubin, E1S and T4S levels.

In conclusion, OATP1B1 is an important factor in hepatic transport and metabolism of bilirubin, E1S and iodothyronine sulfates. OATP1B1-Ala¹⁷⁴ displays decreased transport activity and thereby gives rise to higher bilirubin, E1S and T4S levels in carriers of this polymorphism.