Organic anion transporting polypeptide (Oatp) 1a1-mediated perfluorooctanoate transport and evidence for a renal reabsorption mechanism of Oatp1a1 in renal elimination of perfluorocarboxylates in rats.

摘要

Organic anion transporting polypeptide (Oatp) 1a1 has been hypothesized to play a key role in rat renal reabsorption of perfluorooctanoate (PFO). We have investigated PFO uptake kinetics in Chinese Hamster Ovary (CHO) cells that have been stably transfected with the cDNA encoding Oatp1a1. The Oatp1a1-expressing CHO cells have been validated by their Oatp1a1 gene expression, estrone-3-sulfate (E3S) uptake kinetics, and the correlation between Oatp1a1 gene expression and E3S uptake activity that were both induced by the treatment of sodium butyrate. Oatp1a1-mediated PFO uptake underwent a saturable process with a K(m) value of 162.2+/-20.2microM, which was effectively inhibited by known Oatp1a1 substrates sulfobromophthalein and taurocholate, and a major flavonoid in grapefruit juice, naringin. The inhibition of Oatp1a1-mediated E3S uptake has been compared for linear perfluorocarboxylates with carbon chain lengths ranged from 4 to 12. There was no apparent inhibition by perfluorobutanoate and perfluoropentanoate at 1mM. Inhibition was observed for perfluorohexanoate at 1mM and the level of inhibition increased as the increase of the chain length up to perfluorodecanoate. The values of apparent inhibition constant (K(i,app)) were determined for perfluorocarboxylates with chain lengths between 6 and 10. The log values of K(i,app) exhibited a negative linear relationship to the chain lengths and a positive linear relationship to the log values of the total clearance of perfluorocarboxylates in male rats. This in vitro-to-in vivo correlation strongly supports a tubular reabsorptive role of Oatp1a1 in rat renal elimination of perfluorocarboxylates. Due to the sex-dependent expression of Oatp1a1 in rat kidney, Oatp1a1-mediated tubular reabsorption is suggested to be the mechanism for the sex-dependent renal elimination of PFO in rats.