Sexual Differentiation of Rat Hepatic Bile Salt Sulfotransferase Isoenzymes

Kane, Robert E.; Chen, Lee J.; Herbst, John J.; Thaler, Michael

doi:10.1203/00006450-198808000-00022

Cited by 11 publications

(12 citation statements)

References 24 publications

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“…Furthermore, sulfation of LCA by rat liver was shown to be more than a 100‐fold less than that of humans (Kirkpatrick, Green, Hagey, Hofmann, & Tephly, ). In agreement, rat and hamster sulfotransferases (SULTs) present lower rates of BA sulfation compared with human (Chen & Segel, ; Kane, Chen, Herbst, & Thaler, ). In addition, our current data showed that the tri‐OH BA (CA) had the lowest sulfation, while LCA had the highest sulfation among all the tested BAs (Table ), which agreed with previous reports, where K m for LCA, CDCA and CA sulfation by human liver SULT was 2.5, 25 and 71 μ m , respectively, (Chen & Segel, ) and sulfation activity for G/T‐LCA was four to five times higher than G/T‐CDCA by rat SULTs (Kane et al, ).…”

Section: Discussionmentioning

confidence: 83%

“…In agreement, rat and hamster sulfotransferases (SULTs) present lower rates of BA sulfation compared with human (Chen & Segel, ; Kane, Chen, Herbst, & Thaler, ). In addition, our current data showed that the tri‐OH BA (CA) had the lowest sulfation, while LCA had the highest sulfation among all the tested BAs (Table ), which agreed with previous reports, where K m for LCA, CDCA and CA sulfation by human liver SULT was 2.5, 25 and 71 μ m , respectively, (Chen & Segel, ) and sulfation activity for G/T‐LCA was four to five times higher than G/T‐CDCA by rat SULTs (Kane et al, ). Similarly, we have also previously reported that the K m of LCA, DCA, UDCA and CDCA sulfation by SULT2A1 were 2.0, 8.9, 12.9 and 15.7 μ m , respectively, whereas, the K m of CA could not be determined as no CA‐S formation was detected (Huang, Bathena et al, 2010).…”

Section: Discussionmentioning

confidence: 83%

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Species differences in bile acids II. Bile acid metabolism

Thakare

Alamoudi

Gautam

et al. 2018

J of Applied Toxicology

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One of the mechanisms of drug-induced liver injury (DILI) involves alterations in bile acid (BA) homeostasis and elimination, which encompass several metabolic pathways including hydroxylation, amidation, sulfation, glucuronidation and glutathione conjugation. Species differences in BA metabolism may play a major role in the failure of currently used in vitro and in vivo models to predict reliably the DILI during the early stages of drug discovery and development. We developed an in vitro cofactor-fortified liver S9 fraction model to compare the metabolic profiles of the four major BAs (cholic acid, chenodeoxycholic acid, lithocholic acid and ursodeoxycholic acid) between humans and several animal species. High- and low-resolution liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance imaging were used for the qualitative and quantitative analysis of BAs and their metabolites. Major species differences were found in the metabolism of BAs. Sulfation into 3-O-sulfates was a major pathway in human and chimpanzee (4.8%-52%) and it was a minor pathway in all other species (0.02%-14%). Amidation was primarily with glycine (62%-95%) in minipig and rabbit and it was primarily with taurine (43%-81%) in human, chimpanzee, dog, hamster, rat and mice. Hydroxylation was highest (13%-80%) in rat and mice followed by hamster, while it was lowest (1.6%-22%) in human, chimpanzee and minipig. C6-β hydroxylation was predominant (65%-95%) in rat and mice, while it was at C6-α position in minipig (36%-97%). Glucuronidation was highest in dog (10%-56%), while it was a minor pathway in all other species (<12%). The relative contribution of the various pathways involved in BA metabolism in vitro were in agreement with the observed plasma and urinary BA profiles in vivo and were able to predict and quantify the species differences in BA metabolism. In general, overall, BA metabolism in chimpanzee is most similar to human, while BA metabolism in rats and mice is most dissimilar from human.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 83%

Species differences in bile acids II. Bile acid metabolism

Thakare

Alamoudi

Gautam

et al. 2018

J of Applied Toxicology

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“…A considerable body of information is now available on bile acid/steroid sulphotransferase multiplicity in experimental animals [9][10][11]34,35], but only a few attempts have been made to purify and characterize bile acid sulphotransferases from human tissues. The purpose of the present work is a closer characterization of bile acid sulphation in human liver.…”

Section: Discussionmentioning

confidence: 99%

“…Purification of DHEA sulphotransferase DHEA sulphotransferase was purified from cytosol prepared from individual human livers using DEAE-Sepharose CL-6B andadenosine3',5'-diphosphate-agaroseaffinitychromatography as described previously [34]. Generally, 500-700 mg of cytosolic protein was applied to a DEAE-Sepharose CL-6B column (2 cm x 16 cm) pre-equilibrated with 10 mM-triethanolamine, pH 7.5, containing 1.5 mM-dithiothreitol and 10 % (v/v) glycerol (Buffer A).…”

Section: Human Liver Samplesmentioning

confidence: 99%

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Human liver steroid sulphotransferase sulphates bile acids

Radominska

Comer

Zimniak

et al. 1990

Biochemical Journal

112

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The sulphation of bile acids is an important pathway for the detoxification and elimination of bile acids during cholestatic liver disease. A dehydroepiandrosterone (DHEA) sulphotransferase has been purified from male and female human liver cytosol using DEAE-Sepharose CL-6B and adenosine 3',5'-diphosphate-agarose affinity chromatography [Falany, Vazquez & Kalb (1989) Biochem. J. 260, 641-646]. Results in the present paper show that the DHEA sulphotransferase, purified to homogeneity, is also reactive towards bile acids, including lithocholic acid and 6-hydroxylated bile acids, as well as 3-hydroxylated short-chain bile acids. The highest activity towards bile acids was observed with lithocholic acid (54.3 +/- 3.6 nmol/min per mg of protein); of the substrates tested, the lowest activity was detected with hyodeoxycholic acid (4.2 +/- 0.01 nmol/min per mg of protein). The apparent Km values for the enzyme are 1.5 +/- 0.31 microM for lithocholic acid and 4.2 +/- 0.73 microM for taurolithocholic acid. Lithocholic acid also competitively inhibits DHEA sulphation by the purified sulphotransferase (Ki 1.4 microM). No evidence was found for the formation of bile acid sulphates by sulphotransferases different from the DHEA sulphotransferase during purification work. The above results suggest that a single steroid sulphotransferase with broad specificity encompassing neutral steroids and bile acids exists in human liver.

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Hepatic Bile Salt Sulfotransferases in the Rat

Kane,

Chen

1991

J. pediatr. gastroenterol. nutr.

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SummaryBile salt sulfotransferase (BSS) activity for the fetal bile acid, 3β‐hydroxy‐5‐cholenoate, was first detected in the fetus at 18–19 days of gestation and was twofold greater than for glycolithocholate. The near‐term (20–21 days of gestation) and newborn pup BSS activity was only 5–10% of that in maternal liver. The 3β‐hy‐droxy‐5‐cholenoate sulfotransferase activity rose by the second day of life to levels observed in the mature male, and to activities greater than the mature female by the time of weaning at 3 weeks of age. Sex differences in 3β‐hydroxy‐5‐cholenoate sulfotransferase activity developed during adolescence (28–35 days of age), resulting in fivefold greater activity in the mature female compared with the male. Two isoenzyme activities (BSS I and BSS II) were identified in both sexes during development by DEAE‐Sephadex A‐50 ion‐exchange chromatography of liver cytosol. In the fetal and newborn liver, only one isoenzyme activity was distinctly identified for both monohydroxy bile acids, corresponding to BSS I in older rats. After the first week of life, both BSS I and BSS II exhibited activity like glycolithocholate, but only one peak of activity was identified for 3β‐hydroxy‐5‐cholenoate, corresponding to BSS I. The 3β‐hydroxy‐5‐cholenoate sulfotransferase activity in the mature male was only 20% of the mature female because of a decline in BSS I activity in the male during adolescence. BSS I and II were further purified by taurocholate‐Sepharose 4B chromatography. BSS I had a low affinity toward taurocholate passing through the column, whereas BSS II was absorbed and could be eluted from the column with 0.2 M NaCl. BSS I had four times the activity for 3β‐hydroxy‐5‐cholenoate vs. glycolithocholate, whereas the relative activity of BSS II for 3β‐hydroxy‐5‐cholenoate was only 6% of that for glycolithocholate. BSS I was completely inhibited by 0.1 m M 3‐ketolithocholate, whereas BSS II activity was inhibited only 13%. BSS I activity was enhanced by Co2+ and Zn2+, whereas BSS II activity was inhibited by these divalent ions. We concluded that the monohydroxy bile acids were sulfated by two distinct isoenzymes that could be separated by taurocholate‐Sepharose 4B chromatography. 3β‐Hydroxy‐5‐choleno‐ate was sulfated by BSS I, an isoenzyme regulated by gonadal hormones, which appeared to explain the marked sex differences in 3β‐hydroxy‐5‐cholenoate sulfotransferase activities in mature rats.

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Sexual Differentiation of Rat Hepatic Bile Salt Sulfotransferase Isoenzymes

Cited by 11 publications

References 24 publications

Species differences in bile acids II. Bile acid metabolism

Species differences in bile acids II. Bile acid metabolism

Human liver steroid sulphotransferase sulphates bile acids

Hepatic Bile Salt Sulfotransferases in the Rat

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