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 gender-dependent 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 17β-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 17β-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.
Footnotes
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This work was supported by the National Institutes of Health National Institute of Environmental Health Sciences [Grants ES09649, ES09716, ES07079].
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.024224.
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ABBREVIATIONS: UGT, UDP-glucuronosyltransferase; MPA, mycophenolic acid; AUC, area under the curve; BPA, bisphenol A; P450, cytochrome P450; MRP, multidrug resistance-associated protein; OATP, organic anion-transporting polypeptide; OAT, organic anion transporter; GH, growth hormone; MP, male pattern; FP, female pattern; STAT, signal transducer and activator of transcription; HNF, hepatocyte nuclear factor; HX, hypophysectomy; GNX, gonadectomy; PCR, polymerase chain reaction; MMLV, Moloney murine leukemia virus; bDNA, branched DNA; RT, reverse transcriptase; Ct, cycle threshold.
- Received August 27, 2008.
- Accepted January 7, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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