Gender and species differences in the mammalian organic cation transporters

Sex and species differences in the mammalian organic cation transporters. Organic cation (OC) transporters mediate the transepithelial transport of various endogenous cationic compounds, xenobiotic and drugs in the kidney, intestine, liver, placenta and brain. These transporters are also responsible for (re)absorption or elimination of relevant metabolites. Recent studies have indicated the involvement of OC transportes in drug-drug interactions, drug resistance, and drug-induced organ toxicity. A number of OC transporters from different protein families and species have been cloned and characterized, and their functional roles in kidney and liver have been studied (1). The most important transporters for OC have been grupped into the families SLC22 (OCT1, OCT2, OCT3, OCT6, OCTN1, OCTN2), SLC47 (MATE1, MATE2), and ABCB (MDR1). OCT1, OCT2 and OCT3 represent polyspecific bidirectional transporters that mediate electrogenic, Na+- and pH-independent uptake of OC into cells via facilitated diffusion. In the kidney, these transporter (often sumarized as OCTs) are predominantly localized in basolateral membranes of proximal tubules, where they mediate the first step of the renal OC excretion. The second, exit step across the brush-border membrane is mediated by the electroneutral H+-OC exchangers MATE1 and MATE2-K, and by the ATP-driven efflux pump MDR1. In addition to substrate specificity, transport mechanism and turnover, the OC transporters differ in regulation and localization (1, 2). Recent studies have shown that some of the above mentioned OC transporters exhibit sex differences in renal expression in rat, mouse and rabbit, which correlate with the renal excretion of relevant substrates (3). Sex differences in the expression of some OC transporters were observed concerning distribution within the same organ (different localizations along the nephron) and sex hormone-regulated mRNA and/or protein expression in the same localization. Species differences in some OC transporters have also been demonstrated concerning a) substrate selectivity, b) organ and tissue distribution, c) distribution within individual organs, d) levels of mRNA and/or protein expression in the same localizations, and e) regulation. In the present contribution, examples for each phenomenon collected from the literature or generated in own experiments, will be presented. The presence of sex and species differences of OCT1 and OCT2 will be elaborated in more detail in rat, mouse and human kidneys by showing their expression and different localizations along the nephron. At variance to previous reports, distinct sex differences in expression of both, OCT1 and OCT2 will be demonstrated in rats and mice, but not in humans. Together, the summarized and newly presented data emphasize that the use of rodents in studying (re)absorption, excretion, interaction and toxicity of OC does not reflect the situation in humans. References: 1) Koepsell H et al. (2003) Organic cation transporters. Rev Physiol Biochem Pharmacol 150:103-117 ; 2) Ciarimboli G and Schlatter E (2005) Regulation of organic cation transport. Pfluegers Arch – Eur J Physiol 449:423-441 ; 3) Sabolic I et al. (2007) Gender differences in kidney function. Pfluegers Arch – Eur J Physiol 455:397-429.