Mechanism of gender-divergent UDP-glucuronosyltransferase mRNA expression in mouse liver and kidney

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 17beta-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 17beta-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.

Fig. 1.

Relative mRNA expression of Ugt2b5, Ugt2b37, and Ugt2b38 as determined by real-time PCR in untreated male and female C57BL/6 mouse livers (n = 5/gender/tissue). Data are relative to Ugt2b5 mRNA expression in male liver as determined by ΔΔC_t analysis. Values are expressed as mean ± S.E.M. Asterisks (*) indicate statistically significant differences between male and female mice (p ≤ 0.05).

Fig. 2.

The mRNA expression of Ugt1a1 (A), Ugt1a5 (B), and Ugt2b1 (C) in livers of male and female HX mice treated with growth or sex hormones (n = 4–6/gender/treatment). Treatment groups include CON, naive controls; HX, placebo; HX-MP-GH, male-pattern GH; HX-FP-GH, female-pattern GH, HX-Test, testosterone; and HX-E2, 17β-estradiol. Data are expressed as relative light units/10 μg of total RNA. Values are expressed as mean ± S.E.M. Asterisks (*) indicate statistically significant differences between male and female control mice (p ≤ 0.05). Daggers (†) indicate statistical differences between naive controls and HX mice, and double-daggers (‡) indicate statistical differences between HX-placebo and treated groups (p ≤ 0.05).

Fig. 3.

The mRNA expression of Ugt1a2 (A) and Ugt2b38 (B) in kidneys of male and female HX mice treated with growth or sex hormones (n = 4–6/gender/treatment). Treatment groups include CON, naive controls; HX, placebo; HX-MP-GH, male-pattern GH; HX-FP-GH, female-pattern GH, HX-Test, testosterone; and HX-E2, 17β-estradiol. Data are expressed as relative light units/10 μg of total RNA. Values are expressed as mean ± S.E.M. Asterisks (*) indicate statistically significant differences between male and female control mice (p ≤ 0.05). Daggers (†) indicate statistical differences between naive controls and HX mice, and double-daggers (‡) indicate statistical differences between HX-placebo and treated groups (p ≤ 0.05).

Fig. 4.

The mRNA expression of Ugt1a1 (A), Ugt1a5 (B), and Ugt2b1 (C) in livers of male and female GNX mice treated with sex hormones (n = 6/gender/treatment). Treatment groups include CON, naive controls; GNX, placebo; GNX-Test, testosterone; and GNX-E2, 17β-estradiol. Data are expressed as relative light units/10 μg of total RNA. Values are expressed as mean ± S.E.M. Asterisks (*) indicate statistically significant differences between male and female control mice (p ≤ 0.05). Daggers (†) indicate statistical differences between naive controls and GNX mice, and double-daggers (‡) indicate statistical differences between GNX-placebo and treated groups (p ≤ 0.05).

Fig. 5.

The mRNA expression of Ugt1a2 (A) and Ugt2b38 (B) in kidneys of male and female GNX mice treated with sex hormones (n = 6/gender/treatment). Treatment groups include CON, naive controls; GNX, placebo; GNX-Test, testosterone; and GNX-E2, 17β-estradiol. Data are expressed as relative light units/10 μg of total RNA. Values are expressed as mean ± S.E.M. Asterisks (*) indicate statistically significant differences between male and female control mice (p ≤ 0.05). Daggers (†) indicate statistical differences between naive controls and GNX mice, and double-daggers (‡) indicate statistical differences between GNX-placebo and treated groups (p ≤ 0.05).

Fig. 6.

The mRNA expression of Ugt1a1 (A), Ugt1a5 (B), and Ugt2b1 (C) in livers of male and female lit/lit mice treated with GH (n = 6/gender/treatment). Treatment groups include CON, naive controls; lit/lit, placebo; lit/lit-MP-GH, male-pattern GH; and lit/lit-FP-GH, female-pattern GH. Data are expressed as relative light units/10 μg of total RNA. Values are expressed as mean ± S.E.M. Asterisks (*) indicate statistically significant differences between male and female control mice (p ≤ 0.05). Daggers (†) indicate statistical differences between naive controls and lit/lit mice, and double-daggers (‡) indicate statistical differences between lit/lit-placebo and treated groups (p ≤ 0.05).

Fig. 7.

The mRNA expression of Ugt1a2 (A) and Ugt2b38 (B) in kidneys of male and female lit/lit mice treated with GH (n = 6/gender/treatment). Treatment groups include CON, naive controls; lit/lit, placebo; lit/lit-MP-GH, male-pattern GH; and lit/lit-FP-GH, female-pattern GH. Data are expressed as relative light units/10 μg of total RNA. Values are expressed as mean ± S.E.M. Asterisks (*) indicate statistically significant differences between male and female control mice (p ≤ 0.05). Daggers (†) indicate statistical differences between naive controls and lit/lit mice, and double-daggers (‡) indicate statistical differences between lit/lit-placebo and treated groups (p ≤ 0.05).