Regulation of sulfotransferase mRNA expression in male and female rats of various ages

Abstract

Sulfotransferases (SULTs) are Phase II drug-metabolizing enzymes that catalyze the addition of a sulfuryl moiety to both endogenous compounds, including steroids and neurotransmitters, and certain xenobiotics, including N-hydroxy-2-acetylaminoflourine and phenolic compounds, like α-naphthol. In contrast to certain Phase I drug-metabolizing enzymes, little is known about the regulation of the sulfotransferases. These series of studies were designed to analyze SULT mRNA expression and hormonal regulation in male and female rats. The hepatic expression of six different SULT isoforms was examined including three phenol SULTs and three hydroxysteroid SULTs. SULT mRNA expression was examined in adult and developing rats, as well as, in hypophysectomized (HX) and growth hormone-supplemented HX animals. SULT1A1 is thought to be important for the sulfation of simple phenols and its mRNA expression is about twice as high in adult male as in female rats. This difference in SULT1A1 mRNA levels is largely due to a greater decrease in mRNA levels after puberty in female than in male rats. Hypophysectomy resulted in a decrease in expression of SULT1A1 mRNA in both male and female rats. Replacement of growth hormone (GH) by either intermittent injection (male pattern) or infusion (female pattern) failed to restore SULT1A1 expression. Sulfotransferase SULT1C1 has been implicated in activation of N-hydroxyacetylaminoflourine. In contrast to SULT1A1, SULT1C1 mRNA expression is about 10-fold higher in adult males than in adult female rats. This male-dominant expression pattern emerges at 40–50 days of age and is due to an increase in SULT1C1 mRNA in males. Hypophysectomy abolished SULT1C1 expression in male rats. Interestingly, replacement of GH by injection (male pattern) restored SULT1C1 mRNA expression in males and enhanced SULT1C1 expression in female rats to levels observed in adult male rats. GH infusion (female pattern) did not affect SULT1C1 mRNA expression in either male or female rats. Estrogen sulfotransferase (SULT1E2) may play a role in estrogen homeostasis. Adult male rats express SULT1E2 mRNA at levels 10-fold higher than those observed in adult females and similar to SULT1C1, this is due to an increase in SULT1E2 mRNA occurring during puberty in the male rat. Hypophysectomy did not appreciably affect SULT1E2 expression in male rats, however in contrast to males, hypophysectomy markedly enhanced SULT1E2 expression in female rats. GH infusion suppressed SULT1E2 levels in HX male rats. The expression of hydroxysteroid sulfotransferases was also examined. The SULT-20/21 isoform was expressed in both male and female rats. Male expression of this isoform peaked at 30 days of age and then declined to ∼30% of the level observed in adult females. SULT-20/21 mRNA expression increased sharply at 45 days of age in female rats and remained elevated. Expression of SULT-20/21 mRNA was decreased markedly by hypophysectomy in both male and female rats. GH injection did not affect SULT-20/21 mRNA expression in HX males, however this treatment resulted in a 4-fold increase in SULT-20/21 mRNA in HX females. GH infusion restored SULT-20/21 expression in HX-male rats. GH infusion did elevate SULT-20/21 mRNA expression in female-HX rats, but not to the level observed in intact females. Hydroxysteroid SULT isoform SULT-40/41 was expressed in adult female but not adult male rats. SULT-40/41 expression peaked at 15 days of age in both male and female rats and decreased thereafter. The decrease in expression was more pronounced in male rats. SULT-60 mRNA, like SULT-40/41, was expressed only in adult female rats. Male rats express SULT-60 at 30 days of age, but SULT-60 mRNA is undetectable at 60 days. SULT-60 mRNA was expressed in females only after day 30 and female SULT-60 mRNA expression remains high thereafter. SULT-40/41 and SULT-60 mRNA expression was increased by HX in male rats and decreased by HX in female rats. GH injection suppressed the expression of SULT-40/41 and SULT-60 in males, but did not alter their expression in females. GH infusion did not alter SULT-40/41 or SULT-60 expression in males, but slightly increased the expression of these isoforms in females. In summary, expression of phenol sulfotransferase SULT1A1 was found to be male predominant (2-fold greater) in contrast to isoforms SULT1C1 and SULT1E2, which were male-specific in that they were expressed at 10-fold higher levels in adult male than in female rats. SULT1A1 expression did not appear to be regulated by GH. SULT1C1 expression in males was controlled by the male GH secretory pattern, while in females SULT1E2 expression was suppressed by the female GH secretory pattern. The hydroxysteroid SULTs were primarily expressed in adult female rats, although transient expression in immature male rats was detected. SULT-20/21 was female predominant as it was expressed in adult male rats at 30% of the female level, whereas SULT-40/41 and SULT-60 were female specific as they were undetectable in adult male rats. GH infusion (female pattern) enhanced SULT-20/21 in HX rats, but had less of an effect on SULT-40/41 and SULT-60.