Disease relevance of SULT1A1

• SULT1A1 catalyzes 2-methoxyestradiol sulfonation in MCF-7 breast cancer cells [1].
• MeAalphaC, tested in the presence of rat liver post-mitochondrial fraction, showed strongly enhanced mutagenicity in a Salmonella typhimurium strain expressing human SULT1A1 compared with the control (recipient) strain TA1538/1,8-DNP (deficient in endogenous acetyltransferase) [2].
• We conclude that smoking increases risk of colorectal adenomas and that SULT1A1 and NAT2 only modestly modify this association [3].
• METHODS: In this study, 306 Japanese patients with urothelial transitional cell carcinoma and 306 healthy controls were compared for frequencies of CYP1A2, SULT1A1, and NAT2 genotypes [4].
• We thus hypothesized that the variant SULT1A1 allele may protect against the risk of lung cancer related to tobacco smoking [5].

Psychiatry related information on SULT1A1

• We investigated the association between the SULT1A1 arg/his genotype and esophageal cancer in men, 187 cases of esophageal squamous cell carcinoma and 308 controls from 3 medical centers in Taiwan. Cigarette smoking, areca chewing and alcohol consumption were the major risks for developing esophageal cancer [6].
• In summary, both SULT1A2 and SULT1A1 have a series of common alleles encoding enzymes that differ functionally and are associated with individual differences in phenol SULT properties in the liver [7].
• The results showed that the activity of both of the two forms of PST was significantly higher in 30 patients with obsessive-compulsive disorder and in 25 manic patients than in 20 healthy volunteers [8].
• Phenserine (PS) was designed as a selective acetylcholinesterase (AChE) inhibitor, with a tartrate form (PST) for oral administration in mild to moderate Alzheimer's disease (AD) [9].
• Polymorphism for genotypes of glutathione S-transferase (GST) and sulfotransferase 1A1, hypothetically of importance in dementia disorders, was also included in the analysis [10].

High impact information on SULT1A1

• There may be some interaction between the two alpha subtype-mediated effects in some nephron segments. beta-Adrenergic agonists stimulate cAMP formation in the PST, thick ascending limb (rat and mouse), CNT, and collecting duct segments [11].
• Genetic polymorphisms are observed on such human sulfotransferases as ST1A2, ST1A3, and ST2A3 [12].
• Patient survival was evaluated according to SULT1A1 genotype using Kaplan-Meier survival functions [13].
• BACKGROUND: Human sulfotransferase 1A1 (SULT1A1) catalyzes the sulfation of a variety of phenolic and estrogenic compounds, including 4-hydroxytamoxifen (4-OH TAM), the active metabolite of tamoxifen [13].
• Is ATP (adenosine 5'-triphosphate), like STP, a performance-enhancing additive for the tanks of cancer patients [14]?

Chemical compound and disease context of SULT1A1

• Possible interactions with the SULT1A1 substrate tamoxifen (tam), an anti-estrogen applied in the therapy of breast cancer, were also studied [15].
• Using an RFLP that distinguishes an arginine to histidine change in exon 7 of the SULT1A1 gene, we characterized SULT1A1 genotypes in relation to breast cancer risk [16].
• This study was intended to evaluate the methylation status and transcriptional activity of SULT1A1 in breast cancer tissue (n=56), benign breast tissue (n=20) and morphologically normal breast tissue (n=20), examined by bisulfite genomic sequencing and reverse transcription (RT)-PCR [17].
• We hypothesized that the SULT1A1*2 allozyme has decreased capacity to sulfate estrogens, that the SULT1A1*2 allele conferred increased capacity of cells to proliferate in response to estrogens, and that individuals with the variant SULT1A1 and UGT1A1 genotypes exhibited different breast tumor characteristics [18].
• Our detailed analysis of gene expression profiles of estrogen- and 4-OH-tamoxifen-treated ZR75-1 breast cancer cells identified members of the sulfotransferase 1A (SULT1A) phenol sulfotransferase family as downstream targets of tamoxifen [16].

Biological context of SULT1A1

• The results show that residue Phe-247 of SULT1A1, which interacts with both p-nitrophenol molecules in the active site, is important for substrate inhibition [19].
• These results indicate similar substrate specificities for iodothyronine sulfation by native human liver and kidney sulfotransferases and recombinant SULT1A1 and SULT1A3 [20].
• Also, the smokers carrying the His SULT1A1 allele associated with a low sulfation activity had a 2-fold excess risk compared to never smokers carrying Arg/Arg SULT1A1 common genotype (ORi= 2.55, 95%CI: 1.21-5.36) [21].
• The genes for SULT1A1 and SULT1A2 contain common genetic polymorphisms that are associated with individual variations in levels of enzyme activity as well as variations in biochemical and physical properties [22].
• In summary, we demonstrate the importance of SULT1A1 for the biotransformation of 6-OHMel in human breast cancer cells [15].

Anatomical context of SULT1A1

• The inhibition profiles of the 3,3'-T2 sulfotransferase activities of liver and kidney cytosol obtained by addition of 10 micromol/L of the various analogs were better correlated with the inhibition profile of SULT1A1 than with that of SULT1A3 [20].
• SULT1A1 and SULT1A3 activities were identified in normal and diseased human thyroid glands [23].
• Only expression of SULT1A1 mRNA correlated with the observed conjugation of nanomolar levels of 2-MeOE(2) in these cell lines [1].
• Effects of dexamethasone on aryl (SULT1A1)- and hydroxysteroid (SULT2A1)-sulfotransferase gene expression in primary cultured human hepatocytes [24].
• 5. In conclusion, curcumin is a potent inhibitor of SULT1A1 in human liver, duodenum, colon, kidney and lung [25].

Associations of SULT1A1 with chemical compounds

• The presence of two p-nitrophenol (pNP) molecules in the crystal structure of SULT1A1 was postulated to explain cooperativity at low and inhibition at high substrate concentrations, respectively [19].
• In SULT1A1, substrate inhibition occurs with pNP as the substrate but not with dopamine [19].
• We have investigated the sulfation of the prohormone T4, the active hormone T3, and the metabolites rT3 and 3,3'-diiodothyronine (3,3'-T2) by human liver and kidney cytosol as well as by recombinant human SULT1A1 and SULT1A3, previously known as phenol-preferring and monoamine-preferring phenol sulfotransferase, respectively [20].
• The apparent Km values of 3,3'-T2 and T3 [at 50 micromol/L 3'-phosphoadenosine-5'-phosphosulfate (PAPS)] were 1.02 and 54.9 micromol/L for liver cytosol, 0.64 and 27.8 micromol/L for kidney cytosol, 0.14 and 29.1 micromol/L for SULT1A1, and 33 and 112 micromol/L for SULT1A3, respectively [20].
• Of the latter, SULT1A1 clearly shows the highest affinity for both iodothyronines and PAPS, but it remains to be established whether it is the prominent isoenzyme for sulfation of thyroid hormone in human liver and kidney [20].

Physical interactions of SULT1A1

• PST and membrane-bound COMT were found to have the lowest Km values for both catecholamines [26].

Enzymatic interactions of SULT1A1

• TS PST catalyzes the sulfate conjugation of micromolar concentrations of phenol and p-nitrophenol and TL PST catalyzes the sulfate conjugation of dopamine and other monoamines [27].

Regulatory relationships of SULT1A1

• The ability of hM-PST to sulfate a number of xenobiotics was examined and compared with the bacterially expressed human phenol-sulfating form of PST (hP-PST) [28].
• SULT1A1 mRNA abundance was 39% higher (p < 0.05) in dexamethasone-treated calves compared with control calves. mRNA abundance of CYP2C8 tended also to be higher (+44%; p = 0.053) after dexamethasone treatment [29].
• The natural xanthones reversibly inhibited SULT1A1 with IC50 values ranging from 1.6 to 7 microM whereas much higher amounts of these compounds were required to inhibit SULT2A1 (IC50 values of 26-204 microM) [30].
• Involvement of p38 MAPK and Nrf2 in phenolic acid-induced P-form phenol sulfotransferase expression in human hepatoma HepG2 cells [31].

Other interactions of SULT1A1

• The change of a single amino acid, E146A, was sufficient to transform the catalytic properties and substrate preference of SULT1A3, such that they closely resembled those of SULT1A1 [32].
• We set out to compare the frequencies of common SULT1A1 and SULT1A2 alleles in Caucasian, Chinese and African-American subjects [22].
• Combinations of SULT1A1 fast sulfation (*1/*1) and of NAT2 slow acetylation with smoking resulted in a 4 times higher risk of adenomas compared to never smokers with other inherited gene variants, although there was no statistically significant effect modification [3].
• Alternatively, the Val CYP1B1 or His SULT1A1 allele with modified ability to metabolize estrogens could increase the level of genotoxic catechol estrogen (i.e., 4-hydroxy-estradiol) among smokers [21].
• Several other human SULTs (in particular 1A3 and 1C1) as well as human NAT2 (unlike NAT1) also activated nitrofen, but were markedly less efficient than SULT1A1 [33].

Analytical, diagnostic and therapeutic context of SULT1A1

• Western blot analysis of mammary cytosolic protein showed detectable levels of SULT1A1 and SULT1A3 [34].
• These 33 subjects were genotyped for SULT1A1 by PCR amplification and sequencing of the entire open reading frame (ORF) as well as approximately 1 kb of intron DNA sequence [35].
• Human phenol sulfotransferase STP2 gene: molecular cloning, structural characterization, and chromosomal localization [36].
• The phenol-sulfating form of phenol sulfotransferase (P-PST) was purified and characterized from human liver cytosol using DEAE-cellulose, Sephacryl S-200, and 3',5'-diphosphoadenosine-agarose affinity chromatography [37].
• Utilizing a case-control study design, we hypothesized that the variant allele of the SULT1A1 gene may be associated with lung cancer risk [38].

References