engleski

Gender and species differences in the mammalian organic cation transporters

Organic cation (OC) transporters mediate the transepithelial transport of various endogenous and xenobiotic cationic compounds, including drugs, in various mammalian organs. These transporters are responsible for absorption, reabsorption, and secretion of relevant metabolites in the kidney, intestine, liver, placenta and brain. Recent studies have demonstrated 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 have been studied mainly in the kidney and liver (Koepsell et al.: Organic cation transporters. Rev Physiol Biochem Pharmacol 150:103-117, 2003). The most important OC transporters are grupped into the families SLC22 (OCT1, OCT2, OCT3, OCTN1, OCTN2), SLC47 (MATE1, MATE2), and ABCB (MDR1/P-gp). OCT1-3 represent polyspecific bidirectional transporters that mediate electrogenic, sodium- and pH-independent intracellular uptake of OC via facilitated diffusion. In the renal proximal tubule, these transporter are predominantly localized in the basolateral membrane, 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. Various OC transporters differ in localization, substrate specificity, inhibitor sensitivity, transport mechanism, and regulation (Koepsell et al.: Organic cation transporters. Rev Physiol Biochem Pharmacol 150:103-117, 2003 ; Ciarimboli and Schlatter: Regulation of organic cation transport. Pfluegers Arch Eur J Physiol 449:423-441, 2005). Recent studies have shown that some of the above mentioned OC transporters exhibit sex differences in renal expression in rats, mice and rabbits, which correlate with the renal excretion of relevant substrates (Sabolic et al.: Gender differences in kidney function. Pfluegers Arch Eur J Physiol 455:397-429, 2007). 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 localization, e) sensitivity to inhibitors, and f) regulation. The examples for each phenomenon collected from the literature or obtained in own experiments, will be presented. Sex and species differences in the expression and localization of OCT1 and OCT2 along the rat, mouse, and human nephron will be elaborated in more detail. In contrast to previous reports, distinct sex differences in expression of these OCTs will be demonstrated in rats and mice, but not in humans. Overall, the data indicate that many physiological, pharmacological, and toxicological findings related to OC transport and transporters, obtained in rodents, do not reflect the situation in humans.

sex differences; species differences; organic anions; transporters; mammalian kidney

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