Hormonal regulation of hepatic multidrug resistance-associated protein 2 (Abcc2) primarily involves the pattern of growth hormone secretion

Abstract

Biliary excretion is the rate-limiting step in transfer of bilirubin, other organic anions, and xenobiotics across the liver. Multidrug resistance-associated protein 2 (Mrp2, Abcc2) is the major transporter for conjugated endo- and xenobiotic-conjugated compounds into bile. Hormones regulate bilirubin and xenobiotic secretion into bile, which have dimorphic differences. Therefore, we examined the possible role of sex steroids and growth hormone in the regulation of Mrp2. In ∼8-wk-old rats, mRNA, transcriptional activity, and hepatic content of Mrp2 were selectively increased fourfold ( P < 0.001) in females compared with males. In males, estrogens increased and testosterone decreased Mrp2 mRNA and protein, whereas no significant effect was measured in females, suggesting either a direct effect on the liver or an alteration in growth hormone secretory pattern. After hypophysectomy, Mrp2 mRNA was markedly reduced and the effects of estrogens and testosterone on Mrp2 were prevented, supporting the role of pituitary hormones in controlling Mrp2 expression. Mrp2 increased following growth hormone infusion in males. Mrp2 mRNA was decreased in growth hormone-deficient “Little” mice. Growth hormone infusions in hypophysectomized rats partially restored Mrp2 levels, whereas thyroxine addition returned Mrp2 mRNA and protein to basal levels. Morphology as well as biochemical measurements demonstrated that Mrp2 was localized to the bile canaliculus in equal density in both genders, whereas hormone replacements increased Mrp2 in hypophysectomized animals. In cultured hepatocytes, thyroxine did not have an effect, but growth hormone alone and combined with thyroxine increased Mrp2 mRNA levels. In conclusion, Mrp2 levels are regulated by the combination of thyroxine and different growth hormone secretory patterns.

Effect of Prolactin on Excretory Function of the Liver during the Induction and Relief of Cholestasis in Female Rats

“…Previous studies showed that the expression of this protein is higher in the liver of female rats. It is positively regulated by pituitary hormones of the fa mily of somatotropic hormones [10]. These data suggest that prolactin is a female sex hormone of the pituitary gland, which regulates MRP2 concentration.…”

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

“…Likewise, male-predominant Oatp1a1 expression in mouse liver is caused by the stimulatory effects of male-pattern growth hormone secretion . The influence of growth hormone secretion patterns on the female-predominant expression of hepatic Mrp2 mRNA in rat liver has also been reported (Simon et al, 2006).…”

Expression of Multidrug Resistance Protein 2 (mrp2) in the Liver and Kidney Cells of Female Rats with Modeled Cholestasis of Pregnancy

“…The absence of correlations between the expression of these proteins in hepatocytes and renal structures most likely attests to indirect effect of prolactin related to its infl uence on other systemic regulators. It was shown that estrogens, corticosteroids, and hormones of the thyroid axis affect mrp2 expression in the liver and kidneys and, at the same time, have regulatory interactions with prolactin [5,11,14,15].…”