Purpose: To investigate the association of genetic polymorphisms Gln192Arg and Leu55Met of Paraoxonase 1 (PON1) gene, and Arg213His of Sulfotransferase 1A1 (SUT1A1) gene with occurrence of breast cancer among young women living in Rio de Janeiro city. Methods: This is a hospital-based case-control study including 265 women aged 18-35 years, diagnosed with breast cancer at National Cancer Institute; and 277 controls in the same age group selected among women patients and companions of three general hospitals from Rio de Janeiro public health network. Polymorphisms genotyping was performed using the PCR-RFLP technique. Results: For PON1 gene, breast cancer women had a greater chance of being homozygote for Leu55Met polymorphism (ORadjusted = 1.42, 95% CI= 0.67-3.00, recessive model) and a lower chance of having at least one allele of Gln192Arg polymorphism (ORadjusted = 0.75, 95% CI = 0.50-1.13, dominant model), but without statistical significance. Accordingly, frequency of the haplotype Met55/Arg192 was lower among breast cancer women, but no statistically significant association was observed (ORadjusted = 0.85; 95% CI = 0.48-1.51). SULT1A1 His/His genotype was significantly associated with a protective effect for breast cancer (OR adjusted = 0.51, 95% CI = 0.28-0.91, recessive model). Conclusion: Arg213His polymorphism of SUT1A1 gene showed a protective effect against breast cancer among Brazilian young women. More studies with different designs are needed to understand the role of PON1 and SULT1A1 polymorphisms in breast cancer development in young Brazilian women.

We previously reported on the interaction of 10-chloro-7H-benzo[de]benzo[4,5]imidazo[2,1-a]isoquinolin-7-one (10-Cl-BBQ) with the Aryl hydrocarbon Receptor (AhR) and selective growth inhibition in breast cancer cell lines. We now report on a library of BBQ analogues with substituents on the phenyl and naphthyl rings for biological screening. Herein, we show that absence of the phenyl Cl of 10-Cl-BBQ to produce the simple BBQ molecule substantially enhanced the growth inhibitory effect with GI50 values of 0.001-2.1 μM in select breast cancer cell lines MCF-7, T47D, ZR-75-1, SKBR3, MDA-MB-468, BT20, BT474 cells, while having modest effects of 2.1-7 μM in other cell lines including HT29, U87, SJ-G2, A2780, DU145, BE2-C, MIA, MDA-MB-231 or normal breast cells, MCF10A (3.2 μM). The most potent growth inhibitory effect of BBQ was observed in the triple negative cell line, MDA-MB-468 with a GI50 value of 0.001 μM, presenting a 3,200-fold greater response than in the normal MCF10A breast cells. Additions of Cl, CH3, CN to the phenyl ring and ring expansion from benzoimidazole to dihydroquinazoline hindered the growth inhibitory potency of the BBQ analogues by blocking potential sites of CYP1 oxidative metabolism, while addition of Cl or NO2 to the naphthyl rings restored potency. In a cell-based reporter assay all analogues induced 1.2 to 10-fold AhR transcription activation. Gene expression analysis confirmed the induction of CYP1 oxygenases by BBQ. The CYP1 inhibitor α-naphthoflavone, and the SULT1A1 inhibitor quercetin significantly reduced the growth inhibitory effect of BBQ, confirming the importance of both phase I and II metabolic activation for growth inhibition. Conventional molecular modelling/docking revealed no significant differences between the binding poses of the most and least active analogues. More detailed DFT analysis at the DSD-PBEP86/Def-TZVPP level of theory could not identify significant geometric or electronic changes which would account for this varied AhR activation. Generation of Fukui functions at the same level of theory showed that CYP1 metabolism will primarily occur at the phenyl head group of the analogues, and substituents within this ring lead to lower cytotoxicity.

OBJECTIVE: Certain constituents in migraine food triggers and non-steroidal anti-inflammatory drugs (NSAIDs) inhibit sulfotransferases (SULTs) that detoxify drugs/chemicals and play role in the metabolism of neurotransmitters. We aimed to dissect SULT1A1 modulation of CSD susceptibility and behavior in an in vivo experimental model using hesperidin, a SULT1A1 inhibitor found in citrus fruits (known migraine triggers) and mefenamic acid (SULT1A1 inhibitor), an NSAID to simulate medication overuse.
METHODS: Hesperidin was used as SULT1A1 inhibitor found in citrus fruits, known migraine triggers and mefenamic acid (NSAID), another SULT1A1 inhibitor, was used to induce MO in rats. The groups were; 1) Hesperidin (ip) or its vehicle-DMSO (ip) 2) Chronic (4 weeks) mefenamic acid (ip) or its vehicle (ip) 3) Chronic mefenamic acid+hesperidin (ip) or DMSO (ip). CSD susceptibility was evaluated and behavioral testing was performed. SULT1A1 enzyme activity was measured in brain samples.
RESULTS: Single-dose of hesperidin neither changed CSD susceptibility nor resulted in any behavioral change. Chronic mefenamic acid exposure resulted in increased CSD susceptibility, mechanical-thermal hypersensitivity, increased head shake, grooming and freezing and decreased locomotion. Single dose hesperidin administration after chronic mefenamic acid exposure resulted in increased CSD susceptibility and mechanical-thermal hypersensitivity, increased freezing and decreased locomotion. SULT1A1 enzyme activity was lower in mefenamic acid and mefenamic acid+hesperidin groups compared to their vehicles.
CONCLUSIONS: Mefenamic acid and hesperidin have synergistic effect in modulating CSD susceptibility and pain behavior. Sulfotransferase inhibition may be the common mechanism by which food triggers and NSAIDs modulate migraine susceptibility. Further investigations regarding human provocation studies using hesperidin in migraine patients with medication overuse are needed.

The aim of this study was to investigate the chemical space and interactions of natural compounds with sulfotransferases (SULTs) using ligand- and structure-based in silico methods. An in-house library of natural ligands (hormones, neurotransmitters, plant-derived compounds and their metabolites) reported to interact with SULTs was created. Their chemical structures and properties were compared to those of compounds of non-natural (synthetic) origin, known to interact with SULTs. The natural ligands interacting with SULTs were further compared to other natural products for which interactions with SULTs were not known. Various descriptors of the molecular structures were calculated and analyzed. Statistical methods (ANOVA, PCA, and clustering) were used to explore the chemical space of the studied compounds. Similarity search between the compounds in the different groups was performed with the ROCS software. The interactions with SULTs were additionally analyzed by docking into different experimental and modeled conformations of SULT1A1. Natural products with potentially strong interactions with SULTs were outlined. Our results contribute to a better understanding of chemical space and interactions of natural compounds with SULT enzymes and help to outline new potential ligands of these enzymes.

Sulfotransferases (SULTs) are phase II detoxification enzymes that is involved in the biotransformation of many compounds including tobacco carcinogens. A polymorphism in the SULT1A1 (Arg213His) gene results in reduced enzyme activity.We investigated the association between the SULT1A1 (Arg213/His) genotype and lung cancer (LC). This case-control study comprised of 550 cases and controls, matched on age, gender and smoking status.The variant genotype exhibited no association with LC risk, even after stratification on basis of histological subtypes. Male LC patients carrying the variant His213 allele (p = 0.02) did not exhibit an increased risk towards LC. Smokers harbouring the Arg/His genotype did demonstrate a reduced risk towards LC (AOR = 0.70; p = 0.019). Furthermore, the LC subjects who were heavy smokers and harbouring the Arg/His genotype (AOR = 0.28; p = 0.019) did not show a genetic predisposition towards LC susceptibility. The subjects who smoked pack years of above 40 and carrying the His/His (AOR = 0.28; p = 0.036) genotype were found to have a reduced risk for LC. Furthermore, 473 subjects were analysed in regards to overall survival, wherein the His/His genotype exhibited better OS than Arg/Arg genotype (11.30 vs. 8.07 months).This study provides evidence of no genetic predisposition towards LC risk associated with SULT1A1 Arg213His polymorphism in relation to tobacco smoking.

BACKGROUND: Minoxidil is a widely used over-the-counter topical treatment for hair loss. The response rate for topical minoxidil is relatively low. Minoxidil is a pro-drug, converted to its active form, minoxidil sulfate, by SULT1A1 enzymes located in the scalp. Recently, a novel topical formula that increases the activity of SULT1A1 in hair follicles was reported.
OBJECTIVE: To evaluate any benefit of applying the SULT1A1 enzyme booster prior to daily 5% minoxidil treatment.
METHODS: Male androgenic alopecia patients were recruited to a randomized blinded placebo-controlled study. Patients were randomized to receive 5% topical minoxidil plus the novel formula or minoxidil plus a sham adjuvant. Patient\'s hair growth was monitored using global photography over 60 days.
RESULTS: Twenty-four males with androgenic alopecia (Norwood scale average 4.4, range 2-6) were randomized and completed the trial: 12 in the active arm and 12 in placebo. 75% of the subjects who used the SULT1A1 adjuvant with their daily minoxidil treatments for 60 days regrew hair versus 33% of those using the placebo adjuvant (p = 0.023).
CONCLUSIONS: In a small cohort of androgenetic alopecia men, adding the SULT1A1 adjuvant to their daily minoxidil treatment regimen improved hair regrowth.

p-Cresol sulfate, the primary metabolite of p-cresol, is a uremic toxin that has been associated with toxicities and mortalities. The study objectives were to i) characterize the contributions of human sulfotransferases (SULT) catalyzing p-cresol sulfate formation using multiple recombinant SULT enzymes (including the polymorphic variant SULT1A1*2), pooled human liver cytosols, and pooled human kidney cytosols; and ii) determine the potencies and mechanisms of therapeutic inhibitors capable of attenuating the production of p-cresol sulfate. Human recombinant SULT1A1 was the primary enzyme responsible for the formation of p-cresol sulfate (Km = 0.19 ± 0.02 μM [with atypical kinetic behavior at lower substrate concentrations; see text discussion], Vmax = 789.5 ± 101.7 nmol/mg/min, Ksi = 2458.0 ± 332.8 μM, mean ± standard deviation, n = 3), while SULT1A3, SULT1B1, SULT1E1, and SULT2A1 contributed negligible or minor roles at toxic p-cresol concentrations. Moreover, human recombinant SULT1A1*2 exhibited reduced enzyme activities (Km = 81.5 ± 31.4 μM, Vmax = 230.6 ± 17.7 nmol/mg/min, Ksi = 986.0 ± 434.4 μM) compared to the wild type. The sulfonation of p-cresol was characterized by Michaelis-Menten kinetics in liver cytosols (Km = 14.8 ± 3.4 μM, Vmax = 1.5 ± 0.2 nmol/mg/min) and substrate inhibition in kidney cytosols (Km = 0.29 ± 0.02 μM, Vmax = 0.19 ± 0.05 nmol/mg/min, Ksi = 911.7 ± 278.4 μM). Of the 14 investigated therapeutic inhibitors, mefenamic acid (Ki = 2.4 ± 0.1 nM [liver], Ki = 1.2 ± 0.3 nM [kidney]) was the most potent in reducing the formation of p-cresol sulfate, exhibiting noncompetitive inhibition in human liver cytosols and recombinant SULT1A1, and mixed inhibition in human kidney cytosols. Our novel findings indicated that SULT1A1 contributed an important role in p-cresol sulfonation (hence it can be considered a probe reaction) in liver and kidneys, and mefenamic acid may be utilized as a potential therapeutic agent to attenuate the generation of p-cresol sulfate as an approach to detoxification.

The estrogen receptor (ER)-positive breast cancer represents over 80% of all breast cancer cases. Even though adjuvant hormone therapy with tamoxifen (TMX) is saving lives of patients with ER-positive breast cancer, the acquired resistance to TMX anti-estrogen therapy is the main hurdle for successful TMX therapy. Here we address the mechanism for TMX resistance and explore the ways to eradicate TMX-resistant breast cancer in both in vitro and ex vivo experiments.
To identify compounds able to overcome TMX resistance, we used short-term and long-term viability assays in cancer cells in vitro and in patient samples in 3D ex vivo, analysis of gene expression profiles and cell line pharmacology database, shRNA screen, CRISPR-Cas9 genome editing, real-time PCR, immunofluorescent analysis, western blot, measurement of oxidative stress using flow cytometry, and thioredoxin reductase 1 enzymatic activity.
Here, for the first time, we provide an ample evidence that a high level of the detoxifying enzyme SULT1A1 confers resistance to TMX therapy in both in vitro and ex vivo models and correlates with TMX resistance in metastatic samples in relapsed patients. Based on the data from different approaches, we identified three anticancer compounds, RITA (Reactivation of p53 and Induction of Tumor cell Apoptosis), aminoflavone (AF), and oncrasin-1 (ONC-1), whose tumor cell inhibition activity is dependent on SULT1A1. We discovered thioredoxin reductase 1 (TrxR1, encoded by TXNRD1) as a target of bio-activated RITA, AF, and ONC-1. SULT1A1 depletion prevented the inhibition of TrxR1, induction of oxidative stress, DNA damage signaling, and apoptosis triggered by the compounds. Notably, RITA efficiently suppressed TMX-unresponsive patient-derived breast cancer cells ex vivo.
We have identified a mechanism of resistance to TMX via hyperactivated SULT1A1, which renders selective vulnerability to anticancer compounds RITA, AF, and ONC-1, and provide a rationale for a new combination therapy to overcome TMX resistance in breast cancer patients. Our novel findings may provide a strategy to circumvent TMX resistance and suggest that this approach could be developed further for the benefit of relapsed breast cancer patients.

Sulfotransferase 1A1 (SULT1A1) is responsible for catalyzing various types of endogenous and exogenous compounds. Accumulating data indicates that the polymorphism rs9282861 (R213H) is responsible for inefficient enzymatic activity and associated with cancer progression. To characterize the detailed functional consequences of this mutation behind the loss-of-function of SULT1A1, the present study deployed molecular dynamics simulation to get insights into changes in the conformation and binding energy. The dynamics scenario of SULT1A1 in both wild and mutated types as well as with and without ligand showed that R213H induced local conformational changes, especially in the substrate-binding loop rather than impairing overall stability of the protein structure. The higher conformational changes were observed in the loop3 (residues, 235-263), turning loop conformation to A-helix and B-bridge, which ultimately disrupted the plasticity of the active site. This alteration reduced the binding site volume and hydrophobicity to decrease the binding affinity of the enzyme to substrates, which was highlighted by the MM-PBSA binding energy analysis. These findings highlight the key insights of structural consequences caused by R213H mutation, which would enrich the understanding regarding the role of SULT1A1 mutation in cancer development and also xenobiotics management to individuals in the different treatment stages.

BACKGROUND: Non-opioid and opioid analgesics, as over-the-counter or prescribed medications, are widely used for the management of a diverse array of pathophysiological conditions. Previous studies have demonstrated the involvement of human cytosolic sulfotransferase (SULT) SULT1A1 in the sulfation of acetaminophen, O-desmethylnaproxen (O-DMN), and tapentadol. The current study was designed to investigate the impact of single nucleotide polymorphisms (SNPs) of the human SULT1A1 gene on the sulfation of these analgesic compounds by SULT1A1 allozymes.
METHODS: Human SULT1A1 genotypes were identified by database search. cDNAs corresponding to nine SULT1A1 nonsynonymous missense coding SNPs (cSNPs) were generated by site-directed mutagenesis. Recombinant wild-type and SULT1A1 allozymes were bacterially expressed and affinity-purified. Purified SULT1A1 allozymes were analyzed for sulfation activity using an established assay procedure.
RESULTS: Compared with the wild-type enzyme, SULT1A1 allozymes were shown to display differential sulfating activities toward three analgesic compounds, acetaminophen, O-desmethylnaproxen (O-DMN), and tapentadol, as well as the prototype substrate 4NP.
CONCLUSIONS: Results obtained indicated clearly the impact of genetic polymorphisms on the drug-sulfation activity of SULT1A1 allozymes. Such information may contribute to a better understanding about the differential metabolism of acetaminophen, O-DMN, and tapentadol in individuals with different SULT1A1 genotypes.