Dehydroepiandrosterone sulfate (DHEAS): identification of a carrier protein in human liver and brain

Abstract

Dehydroepiandrosterone sulfate (DHEAS) is the major circulating steroid in man. Pharmacologically, it exerts marked neuropsychiatric effects. Since no target receptor has been identified, we investigated whether the organic anion transporting polypeptide (OATP), a multispecific steroid carrier, transports DHEAS. Expression of the human liver OATP in Xenopus laevis oocytes resulted in high-affinity, partially Na + -dependent uptake of [Q H]DHEAS (K m : 6.6 W Wmol/l). DHEAS transport was inhibited by bromosulfophthalein, bile acids, sulfated estrogens and dexamethasone. Northern blot analysis showed widespread expression of OATP in human brain. These data identify OATP as the first known target protein of DHEAS in human liver and brain.z 1998 Federation of European Biochemical Societies.

Enhanced expression of organic anion transporting polypeptides (OATPs) in androgen receptor-positive prostate cancer cells: Possible role of OATP1A2 in adaptive cell growth under androgen-depleted conditions

“…Several classes of SLC transporters have been shown to mediate DHEAS uptake, including OATP1A2, 1B1, 1B3, and 2B1 [10,11], OAT2, 3, and 4 [20][21][22], and Na + -dependent taurocholate cotransporting polypeptide (NTCP) [23]. Hence, we conducted gene expression profiling of human prostate cancer LNCaP cells cultured under androgen-depleted conditions (Table 2A and Table 3).…”

“…We recently showed that OATP1B3 contributes to estrone 3-sulfate uptake in estrogen receptor-positive human breast cancer MCF-7 cells [9]. In addition to estrone 3-sulfate, these OATPs translocate dehydroepiandrosterone sulfate (DHEAS) [10,11]. DHEAS is a thousand fold more abundant than testosterone in human serum [12], and is essentially unaffected by ADT.…”

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

“…Bilirubin [143] Chenodeoxycholate [144] Chlorambuciltaurocholate [145] Dexamethasone [146] Cholate [144] 93 Cholate [144] Ciprofloxacin [147] Ciprofloxacin [147] DHEAS [40,146] 6.6 E217bG [146] Enoxacin [147] Enoxacin [147] E217bG [40,143] Estrone-3-sulfate [146] Fexofenadine [19,148] 6.4 Erythromycin [148] Estrone-3-sulfate [40,51,149] 16/59 3-Iodothyronamine [150] Gatifloxacin [147] Grepafloxacin [147] Glycocholate [40,144] Taurochenodeoxycholate [144,146,149] Imatinib [151] Indinavir [148] Prostaglandin E2 [40] Levofloxacin [147] 136 Ketokenazole [148] Reverse triiodothyronine [38] Taurocholate [144] Lomefloxacin [147] Lovastatin [148] Taurochenodeoxycholate [144] Tauroursodeoxycholate [144,146] Methotrexate [152] 457 Moxifloxacin [147] Taurocholate [40,…”

Guidance values for microcystins in water and cyanobacterial supplement products (blue-green algal supplements): a reasonable or misguided approach?

“…A most likely explanation for the assumption that primarily hepatotoxicity would occur is the fact that it was realised very early on that MCs cannot permeate across cell membranes but are transported actively into hepatocytes via organic anion transporters (Runnegar et al, 1991), for which bile acid salts (cholate and taurocholate) amongst others, are the bnaturalQ substrates (Frimmer and Ziegler, 1988;Meier, 1996;Meier and Stieger, 2002;Meier et al, 1997;Takikawa, 2002). However, these organic anion transporters are not only expressed in the liver but also in the gastrointestinal tract, the kidney and the brain (blood-brain barrier) (Craddock et al, 1998;Hagenbuch and Meier, 2003;Kullak-Ublick et al, 1998;Kusuhara et al, 1999;Nobre et al, 1999). Indeed, the most recent evidence strongly suggests that MC-LR can be transported across the human blood-brain barrier (Fischer et al, 2004), thus potentially explaining some of the observed neurological symptoms observed in the fatal incident at the renal dialysis station in Cuaruaru, Brazil (Azevedo et al, 2002;Pouria et al, 1998).…”