Human liver steroid sulphotransferase sulphates bile acids

Abstract

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.

Regulation of Sulfotransferase Enzymes by Prototypical Microsomal Enzyme Inducers in Mice

“…We also report the induction of Sult2a1/2a2 mRNA by CAR and PXR activators. Sulfation is the major metabolic pathway for the detoxification of the toxic secondary bile acid, lithocholic acid (LCA), and Sult2a1 is the exclusive enzyme for LCA sulfoconjugation (Radominska et al, 1990). Accumulation of secondary bile acids, especially LCA, is a risk factor for cholestatic liver injury and colorectal cancer (Sonoda et al, 2002).…”

Interactions of the human cytosolic sulfotransferases and steroid sulfatase in the metabolism of tibolone and raloxifene

“…Raloxifene is sulfated in vitro by at least seven expressed human SULT isoforms including SULTs 1E1 and 2A1 (12,17). SULT1E1 is responsible for the high affinity sulfation of estrogens (14,18,19) while SULT2A1 sulfates hydroxysteroids, bile acids and several therapeutic drugs (10,15,20,21). SULT1E1 and SULT2A1 are also of interest since SULT1E1 can form raloxifene disulfate and SULT2A1 can generate the 3-OH Tib disulfates (10,12).…”

The Effects of Endoxifen and Other Major Metabolites of Tamoxifen on the Sulfation of Estradiol Catalyzed by Human Cytosolic Sulfotransferases hSULT1E1 and hSULT1A1*1

“…Calculation of k cat values was based on 68,312 as the dimeric molecular mass of hSULT1A1*1. dmd.aspetjournals.org N-desTAM was a notably good substrate for hSULT1E1 with a calculated k cat /K m higher than the catalytic efficiency constant determined for the sulfation of this metabolite either by hSULT1A1*1 in the current work or by hSULT2A1 in our previous findings (Squirewell et al, 2014). These results suggest that hSULT1E1 might potentially generate sufficient concentrations of N-desTAM-S to inhibit the genotoxic effects of tamoxifen due to the action of hSULT2A1, which is possible given the coexpression of hSULT1E1 and hSULT2A1 in tissues such as the liver (Radominska et al, 1990;Miki et al, 2002) and endometrium Rubin et al, 1999;Singh et al, 2008;Andersson et al, 2010).…”