Presence of organic anion transporters 3 (OAT3) and 4 (OAT4) in human adrenocortical cells

Abstract

Since the organic anion transporter-1 (OAT1) has been implicated in cortisol release from bovine and rat adrenal zona fasciculata cells, we addressed the question of whether OATs are present in human adrenal cortical cells. In the human adrenal cell line NCI-H295R, 24-h cortisol secretion increased up to 30-fold on exposure to forskolin. Incubation of forskolin-treated cells for 24 h with the OAT substrates probenecid, p-aminohippurate (PAH), glutarate or cimetidine inhibited cortisol release partly. RT-PCR did not reveal expression of human OAT1 and OAT2, but OAT3 and OAT4 mRNAs were detected in both NCI-H295R cells and human adrenal tissue. When human OAT3 (hOAT3) and hOAT4 were expressed in Xenopus laevis oocytes, only hOAT3 showed [3H]cortisol uptake in excess of that of water-injected control oocytes. Cortisol uptake via OAT3 was saturable with an apparent Kt of 2.4 microM. In NCI-H295R cells, [3H]estrone sulphate uptake was saturable, cis-inhibited by OAT substrates and trans-stimulated by preloading with glutarate or cortisol. Likewise, [3H]PAH uptake was cis-inhibited by estrone sulphate and trans-stimulated by preloading the cells with PAH, glutarate or cortisol, indicating functional expression of OATs in the plasma membrane of NCI-H295R cells.

Organic Anion Transporters and Their Implications in Pharmacotherapy

“…Although OAT3 mRNA expression was highest in the kidneys of all species, it was also detected in blood-brain barrier (BBB) endothelium, choroid plexus, skeletal muscle, liver, and adrenal gland Alebouyeh et al, 2003;Kikuchi et al, 2003;Kobayashi et al, 2004;Asif et al, 2005). In addition, hOAT3 mRNA levels in the kidney exceeded those described for OAT1 (Motohashi et al, 2002).…”

“…As will be discussed shortly, the ability of OAT3 to transport ES and taurocholate distinguishes it from OAT1 Takeda et al, 2001;Erdman et al, 2006). Furthermore, hOAT3 has been found to transport cAMP, cortisol, prostaglandins E 2 and F 2␣ , DHEAS, estradiol-17␤-glucuronide, taurocholate, and urate Kimura et al, 2002;Kobayashi et al, 2004;Asif et al, 2005;Nilwarangkoon et al, 2007;Chen et al, 2008). A large number of neurotransmitters and their metabolites were tested with human, rat, and mouse transporters.…”

Differential Role of Organic Anion-Transporting Polypeptides in Estrone-3-Sulphate Uptake by Breast Epithelial Cells and Breast Cancer Cells

“…The gene and protein expression of OATPs detected in the different cell systems strongly suggests that the OATPs have a major contribution toward the specific cellular uptake of E3S. However, because E3S is a common substrate for other uptake transporters as well (e.g., OAT3 and OAT4) (Ugele et al, 2003;Asif et al, 2005;Ninomiya et al, 2006), and BSP is also an inhibitor of these transporters, there is a possibility that specific cellular uptake of E3S is contributed by OATPs along with other uptake transporters. No specific carrier-mediated E3S uptake can be detected in the MCF10A immortalized breast epithelial cells (Fig.…”

Role of Mouse Organic Anion Transporter 3 (mOat3) as a Basolateral Prostaglandin E2 Transport Pathway

“…However, recent studies by Aisf et al unveiled the novel role of OAT3 as an efflux pathway of cortisol in endocrine tissues such as adrenocortical cells (43,44). Therefore, the maintenance of homeostasis through the efflux of some endogenous substances such as PGs and steroid hormones would be another important role of the OAT family (9).…”