Abstract
Background & Aims : Sex differences in drug pharmacokinetics have been well recognized and gender has been considered a risk factor for adverse events to medications yet the underlying mechanisms are incompletely understood. The aim of this study was to investigate the effect of gender and dehydroepiandrosterone (DHEA) treatment on the expression of hepatocellular transport proteins involved in uptake and secretion of organic anions in rat. Methods: Expression of the rat liver organic anion transporting polypeptides (Oatps) and multidrug resistance proteins (Mrps) was analyzed by RT-PCR, immunoblot analysis and immunofluorescence microscopy in male and female rats. Regulation of these transport proteins in response to DHEA feeding was investigated. Results: In untreated rats, protein expression significantly differed between genders being higher [Mrp2; Mrp3; Oatp1b2 (Oatp4)] comparable [Oatp1a1 (Oatp1);] or lower [Oatp1a4 (Oatp2)] in female than in male rat. DHEA treatment led to a further increase in Mrp3 expression only in female rats. Mrp2 expression was not influenced by DHEA treatment. In contrast, Oatp1b2 (Oatp4) and Oatp1a1 (Oatp1) were significantly down-regulated after DHEA feeding in both male and female rats. Conclusions: In rat, liver transport proteins of the Oatp and Mrp family are expressed in a gender-specific manner and are differentially regulated in response to DHEA feeding. Down-regulation of uptake transporters and up-regulation of the export pump Mrp3 after DHEA feeding suggests a substrate-dependent feedback regulation. These findings may in part explain the well-known sex differences in hepatic handling of organic anions.
Published Version
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