The Xenobiotics Transporters Mrp2 (Abcc2) and Bcrp (Abcg2): Basal Expression, Regulatory Events and their Mechanisms in Obstructive Cholestasis are Gender-specific

Introduction: Mrp2 (Abcc2) and Bcrp (Abcg2) both are ABC-transporter expressed in the apical membrane of hepatocytes and enterocytes where they restrict uptake and systemic bioavailability of xenobiotics including drugs and carcinogens (Dietrich et al., Gut 2003). Since the extent of (geno-)toxic effects of xenobiotics has widely been shown to be gender-dependent (Ghandi et al., Ann Rev Pharm Tox 2004), we analyzed differences in the basal expression and regulation of both transporters between male and female rats during obstructive cholestasis. Methods: After one week of bile-duct ligation in Sprague-Dawley rats of both gender we obtained small intestine and liver from all animals. Sham-operated rats served as controls. Western and Northern blots were used to determine protein mass and mRNA concentrations of both transporters. Electrophoretic mobility shift assays (EMSA) were done to investigate the binding of Mrp2 gene transactivators. Data are given as mean (SD) % of sham controls. Results: Basal expression of Mrp2 was not gender dependent in liver or intestine. Female hepatic Bcrp expression was only 68 (4) %, however intestinal Bcrp expression amounted to 116 (6) % of male rats. Bcrp downregulation in intestine was significantly more pronounced in female rats (40 (13) % vs. 69 (11) % of controls), while downregulation in liver occurred to a similar extent. In contrast, downregulation of both intestinal and hepatic Mrp2 was significantly more sustained in male rats than in female rats (intestine 17 (4) % vs. 70 (15) % of controls, liver 15 (6) % vs. 45 (7) % of controls). EMSA with rat Mrp2 gene regulatory elements identified decreased RXRα: RARα-binding as responsible mechanism for gender-specific downregulation of Mrp2. Conclusions: The retinoid activated nuclear receptor heterodimer RXRα: RARα mediates gender-specific downregulation of Mrp2 in intestine and liver. The mechanisms of the converse basal expression and downregulation of Bcrp in obstructive cholestasis between sexes remain to be elucidated. Our results confirm widespread gender-dependent mechanisms in transporter gene regulation which may influence bioavailability and metabolism of xenobiotics in a gender-specific fashion.

Key words

gender - toxicity - transport