Mechanism of Gender-Divergent UDP-Glucuronosyltransferase mRNA Expression in Mouse Liver and Kidney

Abstract

ABSTRACT:UDP-glucuronosyltransferases (UGTs) catalyze the addition of glucuronic acid to endo-and xenobiotics, increasing hydrophilicity and enhancing elimination. Gender-divergent glucuronidation rates are observed in humans and rats, and gender differences in UGT mRNA levels have been observed in rodents. The purpose of this study was to establish the hormonal regulation of genderdependent Ugt mRNA expression in mouse liver and kidney. Therefore, three mouse models were used to characterize the involvement of sex hormones and gender-specific growth hormone (GH) secretion patterns, including 1) hypophysectomized mice treated with male-or female-pattern GH, testosterone, or 17␤-estradiol; 2) GH releasing hormone receptor-deficient little (lit/lit) mice treated with male-or female-pattern GH; and 3) gonadectomized mice treated with testosterone or 17␤-estradiol. Messenger RNA expression of mouse Ugt isozymes was determined by the branched DNA assay. In C57BL/6 mice, male-predominant expression of Ugt2b1 and Ugt2b38 was observed in liver and kidney, respectively. Female-predominant expression was observed for Ugt1a1 and Ugt1a5 in liver and Ugt1a2 in kidney. In liver, regulation of Ugt1a1 and Ugt1a5 expression was attributed to repression of Ugt mRNA by male-pattern GH secretion. Conversely, regulation of Ugt2b1 expression in liver was attributed to male-pattern GH secretion. In kidney, regulation of Ugt2b38 expression was attributed to inductive effects by testosterone. Conversely, Ugt1a2 expression in kidney was negatively regulated by testosterone. In conclusion, gender differences in mouse Ugt mRNA expression were influenced by male-pattern GH secretion in liver, whereas gender differences were regulated by the effects of androgens in kidney.UDP-glucuronosyltransferases (UGTs) are a family of microsomal enzymes that catalyze the addition of the high-energy cosubstrate UDP-glucuronic acid to endogenous and exogenous substrates, increasing their hydrophilicity and eventual excretion. UGT genes are composed of two major drug-metabolizing subfamilies, UGT1 and UGT2 (Mackenzie et al., 2005). UGT1 genes are unique in that each consists of a unique first exon and 5Ј-regulatory region; however, each is spliced with common exons 2 through 5. UGT1 enzymes conjugate a variety of compounds, particularly prescribed drugs, such as acetaminophen, and the endogenous heme-byproduct, bilirubin. In contrast, UGT2 genes each contain six individual exons, and UGT2 isozymes conjugate many endogenous steroids and exogenous substrates, such as morphine (Burchell et al., 1995;Tephly et al., 1998;Radominska-Pandya et al., 1999).In clinical studies, numerous glucuronidated drugs exhibit genderrelated differences in metabolism. For example, the benzodiazepine S-oxazepam, a UGT2B15 substrate, is glucuronidated at a higher rate in human liver microsomes from males than females (Court et al.,

Sex-specific gene expression in the BXD mouse liver

“…We found that seven of nine (77.8%) Ugt genes on the array were differentially expressed at q values Յ0.01. Ugt genes were found to be exclusively male biased, which is consistent with the finding that Ugt expression is regulated by male GH production in the liver (8). ABC transporters affect the disposition of many endo-and xenobiotics.…”

Effects of Aging on mRNA Profiles for Drug-Metabolizing Enzymes and Transporters in Livers of Male and Female Mice

“…However, Ugt2b1 mRNA levels decreased between 3 and 27 months of age in both genders. A previous study (Buckley and Klaassen, 2009) reported that the regulation of Ugt2b1 expression in mouse liver was attributable to male-pattern growth hormone secretion. This may explain the dramatic decreases in Ugt2b1 levels for male mice with aging and less dramatic decreases for female mice.…”

“…Gender-divergent expression regulated by growth hormone secretion was reported for P450s (Pampori and Shapiro, 1999), Sults (Liu and Klaassen, 1996;Alnouti and Klaassen, 2006), Ugts (Buckley andGsts (Srivastava andWaxman, 1993;Knight et al, 2007), as well as xenobiotic transporters (Tanaka et al, 2005;Cheng et al, 2006;Maher et al, 2006). Because of the altered sex hormone and growth hormone levels in old age (Rudman et al, 1990;Bjørnerem et al, 2004), it is important to investigate the gender differences in XPG expression during aging.…”

Coordinated Regulation of Hepatic Phase I and II Drug-Metabolizing Genes and Transporters using AhR-, CAR-, PXR-, PPARα-, and Nrf2-Null Mice

“…It is unclear why the remaining differences in constitutive expression occur in one gender but not the other. This laboratory has previously investigated gender-divergent regulation of Ugt and Sult enzymes (Buckley and Klaassen, 2009b;Alnouti and Klaassen, 2011). Sult enzymes are critically regulated by the stimulatory effects of estrogens and growth hormone secretion patterns and suppressed by androgens.…”