REGULATION OF SULFOTRANSFERASE MESSENGER-RNA EXPRESSION IN MALE AND FEMALE RATS OF VARIOUS AGES

Sulfotransferases (SULTs) are Phase II drug-metabolizing enzymes that catalyze the addition of a sulfuryl moiety to both endogenous compound s, including steroids and neurotransmitters, and certain xenobiotics, including N-hydroxy-2-acetylaminofluorine and phenolic compounds, like a-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 ho rmonal regulation in male and female rats. The hepatic expression of s ix different SULT isoforms was examined including three phenol SULTs a nd three hydroxysteroid SULTs. SULT mRNA expression was examined in ad ult and developing rats, as well as, in hypophysectomized (HX) and gro wth hormone-supplemented HX animals. SULT1A1 is thought to be importan t 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 SUL T1A1 mRNA levels is largely due to a greater decrease in mRNA levels a fter 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 (m ale pattern) or infusion (female pattern) failed to restore SULT1A1 ex pression. Sulfotransferase SULT1C1 has been implicated in activation o f N-hydroxyacetylaminofluorine. In contrast to SULT1A1, SULT1C1 mRNA e xpression is about 10-fold higher in adult males than in adult female rats. This male-dominant expression pattern emerges at 40-50 days of a ge 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 observe d in adult male rats. GH infusion (female pattern) did not affect SULT 1C1 mRNA expression in either male or female rats. Estrogen sulfotrans ferase (SULT1E2) may play a role in estrogen homeostasis. Adult male r ats express SULT1E2 mRNA al 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. Hypophysectom y did not appreciably affect SULT1E2 expression in male rats; however in contrast to males, hypophysectomy markedly enhanced SULT1E2 express ion in female rats. GH infusion suppressed SULT1E2 levels in HX male r ats. The expression of hydroxysteroid sulfotransferases was also exami ned. 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 de clined to similar to 30% of the level observed in adult females. SULT- 20/21 mRNA expression increased sharply at 45 days of age in female ra ts 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 tr eatment resulted in a 4-fold increase in SULT-20/21 mRNA in HX females . GR infusion restored SULT-20/21 expression in HX-male rats. GK infus ion did elevate SULT-20/21 mRNA expression in female-HX rats, but not to the level observed in intact females. Hydroxysteroid SULT isoform S ULT-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 pronoun ced 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 S ULT-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 h igh thereafter. SULT-40/41 and SULT-60 mRNA expression was increased b y HX in male rats and decreased by HX in female rats. GH injection sup pressed 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 expressi on of these isoforms in females. In summary, expression of phenol sulf otransferase 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 th an in female rats. SULT1A1 expression did not appear to be regulated b y GH. SULT1C1 expression in males was controlled by the male GH secret ory pattern, while in females SULT1E2, expression was suppressed by th e female GH secretory pattern. The hydroxysteroid SULTs were primarily expressed in adult female rats, although transient expression in imma ture male rats was detected. SULT-20/21 was female predominant as it w as expressed in adult male rats at 30% of the female level, whereas SU LT-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. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.