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

doi:10.1016/S0009-2797(97)00141-5

Chemico-Biological Interactions

Volume 109, Issues 1–3, 20 February 1998, Pages 299-313

https://doi.org/10.1016/S0009-2797(97)00141-5 Get rights and content

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.

Section snippets

Sulfotransferases (SULTs) have generally been regarded as non-inducible enzymes by chemicals and hormones that are considered to be classical inducers of other drug metabolizing enzyme systems like cytochrome P-450s, glucuronosyltransferases and glutathione S-transferases. However, understanding the regulation of SULTs is of crucial importance because these enzymes have been implicated in the metabolic activation of certain chemicals to reactive species that interact with nucleic acids 1, 2. In

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Conjugation of steroids and sterol compounds with a sulfonate group is a major pathway in the regulation of their activity, synthesis and excretion. Three human cytosolic sulfotransferases are highly involved in the sulfonation of sterol compounds. SULT1E1 has a low nM affinity for estrogen sulfonation and also conjugates non-aromatic steroids with a significantly lower affinity. SULT2A1 is responsible for the high levels of fetal and adult dehydroepiandrosterone (DHEA) sulfate synthesis in the adrenal gland as well as many 3α and 3ß-hydroxysteroids and bile acids. SULT2B1b is responsible for the majority of cholesterol sulfation in tissues as well as conjugating 3ß-hydroxysteroids. Although there are multiple methods for assaying cytosolic SULT activity, two relatively simple, rapid and versatile assays for steroid sulfonation are described. The first method utilizes radiolabeled substrates and organic solvent extraction to isolate the radiolabeled product from the aqueous phase. The second assay utilizes ³⁵S-3′-phosphoadenosine 5′-phosphosulfate (PAPS) to generate ³⁵S-conjugated products that are resolved by thin layer chromatography. Both assays useful in situations requiring measurement of SULT activity in a timely manner.
Gender differences in plasma pharmacokinetics and hepatic metabolism of geissoschizine methyl ether from Uncaria hook in rats
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It is speculated that gender-dependent expression of metabolizing enzymes is at least responsible for the gender differences in rat GM plasma pharmacokinetics. Regarding the gender-dependent differences in the drug absorption and excretion processes, both mRNA expressions of hepatic transporter P-glycoprotein in humans (Schuetz et al., 1995) and the phase II metabolism enzyme sulfotransferase 1A1 in rats (Klaassen et al., 1998) have been reported to be two times higher in males than in females. However, in the present study, the Tmax, t1/2, MRT, and ke values reflecting absorption and excretion were not significantly different between male and female rats.
Geissoschizine methyl ether (GM), an indole alkaloid from Uncaria hook, is an active ingredient in the traditional Japanese Kampo medicine yokukansan, which is used to treat neurosis, insomnia, irritability, and night crying in children.
Recent our pharmacokinetic studies suggested that there may be gender differences in the plasma concentrations of GM in rats, but not in humans. However, the details of this difference remain unverified. The purpose of this study was to clarify the reasons for the gender differences in rats.
GM plasma pharmacokinetics was compared in male and female rats orally administered yokukansan (4 g/kg). To confirm the involvement of cytochrome P450 (CYP) in GM liver metabolism, GM was incubated with male and female rat liver S9 fraction in the absence or presence of 1-aminobenzotriazole (a nonspecific CYP inhibitor). CYP isoforms involved in GM metabolism were estimated using recombinant rat CYP isoforms and anti-rat CYP antibodies.
The maximum GM plasma concentrations were significantly higher in female than in male rats. When GM was incubated with rat liver S9 fractions, GM reduction was more striking in male S9 (69.3%) than that in female S9 (10.0%) and was completely blocked with nonspecific CYP inhibitor 1-aminobenzotriazole. Screening experiments using recombinant rat cytochrome P450 (CYP) isoforms showed that CYP1A1, CYP2C6, CYP2C11, CYP2D1, and CYP3A2 were involved in GM metabolism. Of these CYP isoforms, the use of anti-rat CYP antibodies indicated that male-dependent CYP2C11 and CYP3A2 were predominantly involved in the liver microsomal GM metabolism with gender differences.
These results suggest that the cause of gender differences in plasma GM pharmacokinetics in rats is most likely because of male-dependent CYP2C11 and CYP3A2, and provide also useful information to further evaluate the pharmacological and toxicological effects in future. This study is the first to demonstrate that the gender differences in plasma GM pharmacokinetics in rats are caused by the gender-dependent metabolism of GM.
Identification and characterization of a novel PPARα-regulated and 7α-hydroxyl bile acid-preferring cytosolic sulfotransferase mL-STL (Sult2a8)
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Hepatic mouse Sult2a1/2 expression was 100-fold higher in females than in males (51). Rat liver Sult2a1/2 enzyme activities toward hydroxysteroid, including DHEA and bile acid substrates, are also female-predominant (52). No gender difference in catalyzing DHEA was detected in humans (53).
PPARα has been known to play a pivotal role in orchestrating lipid, glucose, and amino acid metabolism via transcriptional regulation of its target gene expression during energy deprivation. Recent evidence has also suggested that PPARα is involved in bile acid metabolism, but how PPARα modulates the homeostasis of bile acids during fasting is still not clear. In a mechanistic study aiming to dissect the spectrum of PPARα target genes involved in metabolic response to fasting, we identified a novel mouse gene (herein named mL-STL for mouse liver-sulfotransferase-like) that shared extensive homology with the Sult2a subfamily of a superfamily of cytosolic sulfotransferases, implying its potential function in sulfonation. The mL-STL gene expressed predominantly in liver in fed state, but PPARα was required to sustain its expression during fasting, suggesting a critical role of PPARα in regulating the mL-STL-mediated sulfonation during fasting. Functional studies using recombinant His-tagged mL-STL protein revealed its narrow sulfonating activities toward 7α-hydroxyl primary bile acids, including cholic acid, chenodeoxycholic acid, and α-muricholic acid, and thus suggesting that mL-STL may be the major hepatic bile acid sulfonating enzyme in mice. Together, these studies identified a novel PPARα-dependent gene and uncovered a new role of PPARα as being an essential regulator in bile acid biotransformation via sulfonation during fasting.
Function and organization of the human cytosolic sulfotransferase (SULT) family
2016, Chemico-Biological Interactions
The sulfuryl transfer reaction is of fundamental biological importance. One of the most important manifestations of this process are the reactions catalyzed by members of the cytosolic sulfotransferase (SULT) superfamily. These enzymes transfer the sulfuryl moiety from the universal donor PAPS (3′-phosphoadenosine 5′-phosphosulfate) to a wide variety of substrates with hydroxyl- or amino-groups. Normally a detoxification reaction this facilitates the elimination of a multitude of xenobiotics, although for some molecules sulfation is a bioactivation step. In addition, sulfation plays a key role in endocrine and other signalling pathways since many steroids, sterols, thyroid hormones and catecholamines exist primarily as sulfate conjugates in humans. This article summarizes much of our current knowledge of the organization and function of the human cytosolic sulfotransferases and highlights some of the important interspecies differences that have implications for, among other things, drug development and chemical safety analysis.
Neonatal isoflavone exposure interferes with the reproductive system of female Wistar rats
2016, Toxicology Letters
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The ratio of sulfated compared to glucuronidated metabolites decreased, which might result from a reduced activity of sulfotransferases (Sult) later in life. This hypothesis is supported by the observation of a decline in hepatic mRNA expression of Sult1a1 in rats at PND30 (Klaassen and Liu, 1998), which is one of the major Sult involved in ISO sulfonation (Nakano et al., 2004). Whether this change in phase II metabolite profile will also occur in humans during aging is, according to our knowledge, still not investigated.
There is increasing concern about possible adverse effects of soy based infant formulas (SBIF) due to their high amount of isoflavones (ISO). The aim of the present study was to investigate effects of neonatal exposure to ISO on reproductive system of female Wistar rats.
Animals were exposed to an ISO depleted diet or a diet enriched with an ISO extract (IRD; 508 mg ISO/kg) during embryogenesis and adolescence. Pups of each group were fed daily by pipette with ISO-suspension (ISO+; 32 mg ISO/kg bw) or placebo from postnatal day (PND) 1 until PND23 resulting in plasma concentrations similar to levels reported in infants fed SBIF.
The visceral fat mass was reduced by long-term IRD. Vaginal epithelial height was increased at PND23 and vaginal opening was precocious in ISO+ groups. Later in life, more often irregular estrus cycles were observed in rats of ISO+ groups. In addition, FSH levels and uterine epithelial heights were increased at PND80 in ISO+ groups.
In summary, the results indicate that neonatal ISO intake, resulting in plasma concentrations achievable through SBIF, has an estrogenic effect on prepubertal rats and influences female reproductive tract later in life.
Sex differences in the constitutive gene expression of sulfotransferases and UDP-glucuronosyltransferases in the pig liver: Androgen-mediated regulation
2014, Drug Metabolism and Pharmacokinetics
Using two breeds (Meishan and Landrace) of pigs and their crossbred offspring (ML, Meishan χ Landrace; LM, Landrace χ Meishan), of which males have genetically different serum androgen levels, we examined whether or not serum androgen plays a crucial role in the constitutive gene expression of hepatic sulfotransferases (SULTs) and UDP-glucuronosyltransferases (UGTs). Real-time RT-PCR analyses showed that in Meishan, ML, and LM pigs, SULT1A1 and SULT2A1 mRNA levels were lower in males having high levels of serum androgen (> 38ng/ml) than in females, whereas those of UGT1A1, UGT1A6, and UGT2B31 were just the opposite. In Landrace pigs having low levels of serum androgen (< 22ng/ml), no such sex differences in expression levels were observed. Moreover, castration of male Meishan pigs altered the gene expression patterns of SULTs and UGTs to female levels. Testosterone-treatment to the castrated males and intact females of either pig breed resulted in decreased SULT1A1 and SULT2A1 and increased UGT1A1, UGT1A6, and UGT2B31 mRNA levels. These findings demonstrate that androgen is one of the physiological factors that determine sexual dimorphism on the constitutive gene expression of SULTs and UGTs in the pig liver.

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

Abstract

Section snippets

J. Biol. Chem.

J. Steroid Biochem. Mol. Biol.

J. Steroid Biochem. Mol. Biol.

Eur. J. Cancer

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Chem.-Biol. Interact.

J. Biol. Chem.

Arch. Biochem. Biophys.

Biochim. Biophys. Acta

Biochim. Biophys. Acta

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Role of sulfation in the formation of DNA adducts from N-hydroxy-2-acetylaminofluorene in rat liver in vivo. Inhibition of N-acetylated aminofluorene adduct formation by pentachlorophenol

Carcinogenesis

Sulphation of tyrosine residues—a widespread modification of proteins

Nature