-
Chemical Research in Toxicology Oct 2022Nitro group containing xenobiotics include drugs, cancer chemotherapeutic agents, carcinogens (e.g., nitroarenes and aristolochic acid) and explosives. The nitro group... (Review)
Review
Nitro group containing xenobiotics include drugs, cancer chemotherapeutic agents, carcinogens (e.g., nitroarenes and aristolochic acid) and explosives. The nitro group undergoes a six-electron reduction to form sequentially the nitroso-, -hydroxylamino- and amino-functional groups. These reactions are catalyzed by nitroreductases which, rather than being enzymes with this sole function, are enzymes hijacked for their propensity to donate electrons to the nitro group either one at a time via a radical mechanism or two at time via the equivalent of a hydride transfer. These enzymes include: NADPH-dependent flavoenzymes (NADPH: P450 oxidoreductase, NAD(P)H-quinone oxidoreductase), P450 enzymes, oxidases (aldehyde oxidase, xanthine oxidase) and aldo-keto reductases. The hydroxylamino group once formed can undergo conjugation reactions with acetate or sulfate catalyzed by -acetyltransferases or sulfotransferases, respectively, leading to the formation of intermediates containing a good leaving group which in turn can generate a nitrenium or carbenium ion for covalent DNA adduct formation. The intermediates in the reduction sequence are also prone to oxidation and produce reactive oxygen species. As a consequence, many nitro-containing xenobiotics can be genotoxic either by forming stable covalent adducts or by oxidatively damaging DNA. This review will focus on the general chemistry of nitroreduction, the enzymes responsible, the reduction of xenobiotic substrates, the regulation of nitroreductases, the ability of nitrocompounds to form DNA adducts and act as mutagens as well as some future directions.
Topics: Acetyltransferases; Aldehydes; Aldo-Keto Reductases; Carcinogens; DNA Adducts; Environmental Pollutants; Explosive Agents; Metabolic Networks and Pathways; Mutagens; NAD; NAD(P)H Dehydrogenase (Quinone); NADP; Quinones; Reactive Oxygen Species; Sulfates; Sulfotransferases; Xanthine Oxidase; Xenobiotics
PubMed: 36044734
DOI: 10.1021/acs.chemrestox.2c00175 -
Molecules (Basel, Switzerland) Oct 2023The aim of this study was to develop and optimize a chiral HPLC-MS/MS method for quantitative analysis of ()-/()-salbutamol and ()-/()-salbutamol-4'--sulfate in human...
Development of an HPLC-MS/MS Method for Chiral Separation and Quantitation of ()- and ()-Salbutamol and Their Sulfoconjugated Metabolites in Urine to Investigate Stereoselective Sulfonation.
The aim of this study was to develop and optimize a chiral HPLC-MS/MS method for quantitative analysis of ()-/()-salbutamol and ()-/()-salbutamol-4'--sulfate in human urine to allow for bioanalytical quantitation of the targeted analytes and investigations of stereoselectivity in the sulfonation pathway of human phase Ⅱ metabolism. For analytical method development, a systematic screening of columns and mobile phases to develop a separation via enantiomerically selective high performance liquid chromatography was performed. Electrospray ionization settings were optimized via multiple-step screening and a full factorial design-of-experiment. Both approaches were performed matrix-assisted and the predicted values were compared. The full factorial design was superior in terms of prediction power and knowledge generation. Performing a longitudinal excretion study in one healthy volunteer allowed for the calculation of excretion rates for all four targeted analytes. For this proof-of-concept, either racemic salbutamol or enantiopure levosalbutamol was administered perorally or via inhalation, respectively. A strong preference for sulfonation of ()-salbutamol for inhalation and peroral application was found in experiments. In previous studies phenol sulfotransferase 1A3 was described to be mainly responsible for salbutamol sulfonation in humans. Thus, in vitro and in silico investigations of the stereoselectivity of sulfotransferase 1A3 complemented the study and confirmed these findings.
Topics: Humans; Albuterol; Chromatography, High Pressure Liquid; Tandem Mass Spectrometry; Levalbuterol; Administration, Inhalation; Stereoisomerism
PubMed: 37894685
DOI: 10.3390/molecules28207206 -
Journal of Experimental Botany Jul 2021Tyrosine-sulfated peptides are key regulators of plant growth and development. The disulfated pentapeptide phytosulfokine (PSK) mediates growth via leucine-rich repeat...
Tyrosine-sulfated peptides are key regulators of plant growth and development. The disulfated pentapeptide phytosulfokine (PSK) mediates growth via leucine-rich repeat receptor-like kinases, PSKR1 and PSKR2. PSK receptors (PSKRs) are part of a response module at the plasma membrane that mediates short-term growth responses, but downstream signaling of transcriptional regulation remains unexplored. In Arabidopsis, tyrosine sulfation is catalyzed by a single-copy gene (TPST; encoding tyrosylprotein sulfotransferase). We performed a microarray-based transcriptome analysis in the tpst-1 mutant background that lacks sulfated peptides to identify PSK-regulated genes and genes that are regulated by other sulfated peptides. Of the 169 PSK-regulated genes, several had functions in root growth and development, in agreement with shorter roots and a higher lateral root density in tpst-1. Further, tpst-1 roots developed higher numbers of root hairs, and PSK induced expression of WEREWOLF (WER), its paralog MYB DOMAIN PROTEIN 23 (MYB23), and At1g66800 that maintain non-hair cell fate. The tpst-1 pskr1-3 pskr2-1 mutant showed even shorter roots, and higher lateral root and root hair density than tpst-1, revealing unexpected synergistic effects of ligand and PSKR deficiencies. While residual activities may exist, overexpression of PSKR1 in the tpst-1 background induced root growth, suggesting that PSKR1 may be active in the absence of sulfated ligands.
Topics: Arabidopsis; Arabidopsis Proteins; Receptors, Cell Surface; Signal Transduction; Sulfotransferases
PubMed: 34028532
DOI: 10.1093/jxb/erab233 -
[Identification of SULF1 as a Shared Gene in Idiopathic Pulmonary Fibrosis and Lung Adenocarcinoma].Zhongguo Fei Ai Za Zhi = Chinese... Sep 2023Idiopathic pulmonary fibrosis (IPF) is an idiopathic chronic, progressive interstitial lung disease with a diagnosed median survival of 3-5 years. IPF is associated with...
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is an idiopathic chronic, progressive interstitial lung disease with a diagnosed median survival of 3-5 years. IPF is associated with an increased risk of lung cancer. Therefore, exploring the shared pathogenic genes and molecular pathways between IPF and lung adenocarcinoma (LUAD) holds significant importance for the development of novel therapeutic approaches and personalized precision treatment strategies for IPF combined with lung cancer.
METHODS
Bioinformatics analysis was conducted using publicly available gene expression datasets of IPF and LUAD from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis was employed to identify common genes involved in the progression of both diseases, followed by functional enrichment analysis. Subsequently, additional datasets were used to pinpoint the core shared genes between the two diseases. The relationship between core shared genes and prognosis, as well as their expression patterns, clinical relevance, genetic characteristics, and immune-related functions in LUAD, were analyzed using The Cancer Genome Atlas (TCGA) database and single-cell RNA sequencing datasets. Finally, potential therapeutic drugs related to the identified genes were screened through drug databases.
RESULTS
A total of 529 shared genes between IPF and LUAD were identified. Among them, SULF1 emerged as a core shared gene associated with poor prognosis. It exhibited significantly elevated expression levels in LUAD tissues, concomitant with high mutation rates, genomic heterogeneity, and an immunosuppressive microenvironment. Subsequent single-cell RNA-seq analysis revealed that the high expression of SULF1 primarily originated from tumor-associated fibroblasts. This study further demonstrated an association between SULF1 expression and tumor drug sensitivity, and it identified potential small-molecule drugs targeting SULF1 highly expressed fibroblasts.
CONCLUSIONS
This study identified a set of shared molecular pathways and core genes between IPF and LUAD. Notably, SULF1 may serve as a potential immune-related biomarker and therapeutic target for both diseases.
Topics: Humans; Lung Neoplasms; Adenocarcinoma of Lung; Idiopathic Pulmonary Fibrosis; Adenocarcinoma; Cancer-Associated Fibroblasts; Prognosis; Tumor Microenvironment; Sulfotransferases
PubMed: 37985153
DOI: 10.3779/j.issn.1009-3419.2023.101.25 -
BMC Biology Jul 2023Chronic kidney disease (CKD) accelerates atherosclerosis, but the mechanisms remain unclear. Tyrosine sulfation has been recognized as a key post-translational...
BACKGROUND
Chronic kidney disease (CKD) accelerates atherosclerosis, but the mechanisms remain unclear. Tyrosine sulfation has been recognized as a key post-translational modification (PTM) in regulation of various cellular processes, and the sulfated adhesion molecules and chemokine receptors have been shown to participate in the pathogenesis of atherosclerosis via enhancement of monocyte/macrophage function. The levels of inorganic sulfate, the essential substrate for the sulfation reaction, are dramatically increased in patients with CKD, which indicates a change of sulfation status in CKD patients. Thus, in the present study, we detected the sulfation status in CKD patients and probed into the impact of sulfation on CKD-related atherosclerosis by targeting tyrosine sulfation function.
RESULTS
PBMCs from individuals with CKD showed higher amounts of total sulfotyrosine and tyrosylprotein sulfotransferase (TPST) type 1 and 2 protein levels. The plasma level of O-sulfotyrosine, the metabolic end product of tyrosine sulfation, increased significantly in CKD patients. Statistically, O-sulfotyrosine and the coronary atherosclerosis severity SYNTAX score positively correlated. Mechanically, more sulfate-positive nucleated cells in peripheral blood and more abundant infiltration of sulfated macrophages in deteriorated vascular plaques in CKD ApoE null mice were noted. Knockout of TPST1 and TPST2 decreased atherosclerosis and peritoneal macrophage adherence and migration in CKD condition. The sulfation of the chemokine receptors, CCR2 and CCR5, was increased in PBMCs from CKD patients.
CONCLUSIONS
CKD is associated with increased sulfation status. Increased sulfation contributes to monocyte/macrophage activation and might be involved in CKD-related atherosclerosis. Inhibition of sulfation may suppress CKD-related atherosclerosis and is worthy of further study.
Topics: Mice; Animals; Sulfotransferases; Proteins; Tyrosine; Mice, Knockout; Receptors, Chemokine; Atherosclerosis; Protein Processing, Post-Translational
PubMed: 37424015
DOI: 10.1186/s12915-023-01641-y -
Molecular Biology Reports Jun 2020Human estrogen sulfotransferase (SULT1E1) and nuclear factor erythroid 2-related factor 2 (Nrf-2) expression influences each other in advanced human breast... (Review)
Review
Human estrogen sulfotransferase (SULT1E1) and nuclear factor erythroid 2-related factor 2 (Nrf-2) expression influences each other in advanced human breast carcinogenesis. The difference in the metabolism of estradiol (E2) in pre- and post-menopausal women remains to be connected with post-menopausal breast cancer. A synergism between ROS production and E2 generation has been demonstrated. No definite mechanism for simultaneous functions of Nrf2, oxidative stress E2 regulating enzymes (SULT1E1) has been yet clarified. Our present review demonstrates that ROS dependent regulation of Nrf-2 is one of the most important determinants of E2 regulation by altering SULT1E1 expression. This study also focuses the idea that estrogen receptor cased subtypes of cancer may have different molecular environments which has an impact on the therapeutic efficacy.
Topics: Breast Neoplasms; Cell Line, Tumor; Estradiol; Estrogens; Female; Humans; NF-E2-Related Factor 2; Oxidative Stress; Sulfotransferases; Transcription Factors
PubMed: 32449069
DOI: 10.1007/s11033-020-05518-z -
Animals : An Open Access Journal From... Nov 2021Boars express high testicular levels of sulfotransferase enzymes, and consequently, the boar taint causing compound androstenone predominantly circulates as a steroid...
Boars express high testicular levels of sulfotransferase enzymes, and consequently, the boar taint causing compound androstenone predominantly circulates as a steroid sulfate. Androstenone sulfate is suspected to function as a steroid reservoir that can be deconjugated to provide a source of free androstenone for accumulation. Therefore, the purpose of this study was to characterize the uptake and deconjugation of androstenone sulfate in the adipose tissue of the boar. Real-time PCR was used to quantify the expression of steroid sulfatase (STS) and several organic anion transporting polypeptides (OATPs) in the adipose tissue. Additionally, [H]-androstenone sulfate was incubated with adipocytes or supernatant from homogenized fat to assess steroid uptake and conversion, respectively. A positive correlation existed between OATP-B expression and androstenone sulfate uptake (r = 0.86, = 0.03), as well as between STS expression and androstenone sulfate conversion (r = 0.76, < 0.001). Moreover, fat androstenone concentrations were positively correlated (r = 0.85, < 0.001) with androstenone sulfate conversion and tended to increase with STS expression in early maturing boars. This suggests that androstenone sulfate uptake and deconjugation are mediated by OATP-B and STS, respectively, which may influence the development of boar taint in early maturing animals.
PubMed: 34827890
DOI: 10.3390/ani11113158 -
Cancer Medicine May 2023Hepatocellular carcinoma (HCC) is aggressive liver cancer. Despite advanced imaging and other diagnostic measures, HCC in a significant portion of patients had reached...
BACKGROUND
Hepatocellular carcinoma (HCC) is aggressive liver cancer. Despite advanced imaging and other diagnostic measures, HCC in a significant portion of patients had reached the advanced stage at the first diagnosis. Unfortunately, there is no cure for advanced HCC. As a result, HCC is still a leading cause of cancer death, and there is a pressing need for new diagnostic markers and therapeutic targets.
METHODS
We investigated sulfotransferase 1C2 (SUTL1C2), which we recently showed was overexpressed in human HCC cancerous tissues. Specifically, we analyzed the effects of SULT1C2 knockdown on the growth, survival, migration, and invasiveness of two HCC cell lines, i.e., HepG2 and Huh7 cells. We also studied the transcriptomes and metabolomes in the two HCC cell lines before and after SULT1C2 knockdown. Based on the transcriptome and metabolome data, we further investigated the SULT1C2 knockdown-mediated shared changes, i.e., glycolysis and fatty acid metabolism, in the two HCC cell lines. Finally, we performed rescue experiments to determine whether the inhibitory effects of SULT1C2 knockdown could be rescued via overexpression.
RESULTS
We showed that SULT1C2 overexpression promoted the growth, survival, migration, and invasiveness of HCC cells. In addition, SULT1C2 knockdown resulted in a wide range of gene expression and metabolome changes in HCC cells. Moreover, analysis of shared alterations showed that SULT1C2 knockdown significantly suppressed glycolysis and fatty acid metabolism, which could be rescued via SULT1C2 overexpression.
CONCLUSIONS
Our data suggest that SULT1C2 is a potential diagnostic marker and therapeutic target for human HCC.
Topics: Humans; Mice; Liver Neoplasms; Carcinoma, Hepatocellular; Sulfotransferases; Glycolysis; Fatty Acids; Cell Line, Tumor; Metabolomics; Mice, Inbred BALB C; Gene Knockdown Techniques; Cell Movement; Neoplasm Invasiveness; Gene Expression; Animals
PubMed: 36880364
DOI: 10.1002/cam4.5759 -
Chemical Research in Toxicology Aug 2022The cochaperone Aha1 activates HSP90 ATPase to promote the folding of its client proteins; however, very few client proteins of Aha1 are known. With the use of an...
The cochaperone Aha1 activates HSP90 ATPase to promote the folding of its client proteins; however, very few client proteins of Aha1 are known. With the use of an ascorbate peroxidase (APEX)-based proximity labeling method, we identified SULT1A1 as a proximity protein of HSP90 that is modulated by genetic depletion of Aha1. Immunoprecipitation followed by Western blot analysis showed the interaction of SULT1A1 with Aha1, but not HSP90. We also observed a reduced level of SULT1A1 protein upon genetic depletion of Aha1 but not upon pharmacological inhibition of HSP90, suggesting that the SULT1A1 protein level is regulated by Aha1 alone. Maturation-dependent interaction assay results showed that Aha1, but not HSP90, binds preferentially to newly synthesized SULT1A1. Reconstitution of Aha1-depleted cells with wild-type Aha1 and its E67K mutant, which is deficient in interacting with HSP90, restored SULT1A1 protein to the same level. Nonetheless, complementation of Aha1-depleted cells with an Aha1 mutant lacking the first 20 amino acids, which disrupts its autonomous chaperone function, was unable to rescue the SULT1A1 protein level. Together, our study revealed, for the first time, Aha1 as an autonomous chaperone in regulating SULT1A1. SULT1A1 is a phase-II metabolic enzyme, where it adds sulfate groups to hydroxyl functionalities in endogenous hormones and xenobiotic chemicals to improve their solubilities and promote their excretion. Thus, our work suggests the role of Aha1 cochaperone in modulating the detoxification of endogenous and environmental chemicals.
Topics: Adenosine Triphosphatases; Arylsulfotransferase; HSP90 Heat-Shock Proteins; Humans; Molecular Chaperones
PubMed: 35926086
DOI: 10.1021/acs.chemrestox.2c00167