SULT1A2 Human

What is human SULT1A2 and what is its primary function in xenobiotic metabolism?

SULT1A2 is a member of the sulfotransferase 1 family that functions as a catalyst for sulfate conjugation reactions. It utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as a sulfonate donor to catalyze the sulfate conjugation of catecholamines, phenolic drugs, and neurotransmitters . The primary metabolic function of SULT1A2 involves transforming hydrophobic compounds into more hydrophilic forms, thereby facilitating their elimination from the organism . This enzyme plays a crucial role in the biotransformation of various xenobiotics, including therapeutic drugs and environmental toxicants.
SULT1A2 is also responsible for the sulfonation and activation of minoxidil and mediates the metabolic activation of carcinogenic N-hydroxyarylamines to DNA binding products . This dual capability for both detoxification and bioactivation makes SULT1A2 particularly interesting in pharmacological and toxicological research contexts.
Methodologically, researchers can characterize SULT1A2 function through enzyme activity assays using recombinant protein (295 amino acids) with various substrate classes to determine specificity and kinetic parameters .

How does SULT1A2 differ structurally and functionally from other sulfotransferase family members?

SULT1A2 belongs to the SULT1 family along with SULT1A1, both classified as aryl/phenol or thermostable sulfotransferases with broad substrate specificity for phenolic compounds . The human sulfotransferase superfamily can be differentiated as follows:

What are the preferred substrates for human SULT1A2 and how does substrate specificity compare to SULT1A1?

SULT1A2 exhibits a broad but defined substrate specificity profile. The primary substrates include:

• Phenolic compounds: As an aryl sulfotransferase, SULT1A2 has high affinity for compounds containing phenolic groups

• Catecholamines: The enzyme efficiently catalyzes sulfate conjugation of various catecholamines

• Phenolic drugs: SULT1A2 metabolizes numerous pharmaceutical compounds containing phenolic moieties

• Neurotransmitters: Various neurotransmitters serve as substrates for SULT1A2-mediated sulfation

• Minoxidil: SULT1A2 is specifically responsible for the sulfonation and activation of this drug

• N-hydroxyarylamines: The enzyme mediates the metabolic activation of these carcinogenic compounds to DNA binding products
  While SULT1A1 and SULT1A2 share similar substrate preferences due to their close structural relationship, there are subtle differences in their affinity and catalytic efficiency for specific compounds. Both enzymes are known to metabolize phenolic compounds, but may differ in their capacity to activate certain procarcinogens . Research methodologies to distinguish between these closely related enzymes typically involve selective inhibitors or substrate competition assays.

How is SULT1A2 gene expression regulated in human tissues?

• Sex-dependent regulation: Expression of liver SULT1A1/2 shows sex-dependent patterns associated with susceptibility to bladder and liver carcinogenesis. Studies have demonstrated that androgen-dependent suppression of ABP (4-aminobiphenyl) sulfation in the liver leads to increased bladder delivery of carcinogenic ABP in males .

• Tissue-specific expression: While comprehensive tissue expression data for SULT1A2 is not provided in the search results, it appears to be expressed in the liver and bladder tissues based on the studies cited .

• Pathological states: SULT1A2 expression is significantly elevated in bladder cancer tissues compared to adjacent normal bladder tissues, suggesting disease-specific regulation of this gene .
  Researchers investigating SULT1A2 regulation should consider employing techniques such as promoter analysis, transcription factor binding studies, and epigenetic profiling to fully characterize the regulatory mechanisms controlling SULT1A2 expression across different tissues and physiological states.

What methodologies are available for measuring SULT1A2 activity in biological samples?

Several complementary methodologies can be employed to measure SULT1A2 activity in biological samples:

• Transcriptomic analysis:

  • RT-qPCR for mRNA quantification in cell and tissue samples

  • RNA-seq data analysis from databases like TCGA and GEO

• Protein expression analysis:

  • Western blot analysis using specific antibodies against SULT1A2

  • Immunohistochemistry (IHC) for tissue localization and semi-quantitative assessment

• Enzymatic activity assays:

  • Spectrophotometric assays measuring sulfate transfer to model substrates

  • Radiometric assays using labeled substrates or co-factors

  • HPLC-based methods to detect sulfated metabolites

  • Recombinant protein assays using purified SULT1A2 protein

• Genetic analysis:

  • Genotyping for polymorphisms that may affect enzyme activity

  • Gene expression correlation with substrate metabolism
    For optimal experimental design, researchers should consider combining multiple methods to establish relationships between gene expression, protein levels, and enzymatic activity in their biological system of interest.

How do genetic polymorphisms in SULT1A2 affect enzyme activity and disease susceptibility?

While the search results don't provide direct information on SULT1A2 polymorphisms specifically, insights can be drawn from studies on related sulfotransferases:
For the related enzyme SULT1A1, the Arg213His polymorphism has been extensively studied in relation to cancer risk. A meta-analysis indicated that this polymorphism is not associated with lung cancer risk in Asians and Caucasians , but similar functional variants might exist in SULT1A2 given the close relationship between these genes.
Methodologically, researchers investigating SULT1A2 polymorphisms should:

What is the role of SULT1A2 in carcinogen metabolism and how does it influence cancer risk?

SULT1A2 plays a complex role in carcinogen metabolism with paradoxical implications for cancer risk:

• Employ metabolomic approaches to track carcinogen metabolism

• Use DNA adduct analysis to directly measure genotoxic effects

• Develop animal models with tissue-specific SULT1A2 expression modulation

• Conduct epidemiological studies correlating SULT1A2 genetic variants with cancer incidence
  This complex relationship highlights the importance of context-specific research when studying SULT1A2's role in carcinogenesis.

How does SULT1A2 expression correlate with cancer prognosis and what are the potential mechanisms?

Research indicates a significant relationship between SULT1A2 expression and cancer prognosis, particularly in bladder cancer:

What signaling pathways interact with SULT1A2 in disease contexts and how might these be therapeutically targeted?

Gene set enrichment analysis has identified several key signaling pathways associated with SULT1A2 in bladder cancer:

• Direct enzyme modulation: Developing specific inhibitors or activators of SULT1A2 based on its crystal structure

• Pathway targeting: Using existing inhibitors of PI3K-Akt or MAPK pathways in tumors with specific SULT1A2 expression patterns

• Combination approaches: Targeting both SULT1A2 and its associated signaling pathways simultaneously

• Biomarker-guided therapy: Using SULT1A2 expression as a biomarker for response to specific targeted therapies
  Methodologically, researchers should employ pharmacological inhibitors, genetic knockdown/knockout approaches, and pathway activation/inhibition studies to fully characterize these interactions and their therapeutic potential.

What role does SULT1A2 play in liver diseases such as NAFLD and NASH?

• Some studies report increased expression of SULT1A1 in patients with NASH

• Other research indicates a significant decrease in SULT1A1 activity with increasing severity of liver disease from simple steatosis to cirrhosis

• In human liver tissues, sulfation of bisphenol A was substantially lower in livers from subjects with steatosis (23%), diabetic cirrhosis (16%), and cirrhosis (18%) relative to healthy livers (100%)
  Given the structural and functional similarities between SULT1A1 and SULT1A2, it's reasonable to hypothesize that SULT1A2 activity might also be altered in liver diseases, potentially affecting the metabolism of both endogenous and exogenous compounds.
  Research methodologies to investigate SULT1A2 in liver diseases should include:

• Expression analysis in liver biopsy samples from patients with various stages of NAFLD/NASH

• Functional studies measuring SULT1A2 activity in healthy versus diseased liver samples

• Animal models of NAFLD/NASH with genetic modulation of SULT1A2

• Correlation of SULT1A2 polymorphisms with NAFLD/NASH susceptibility and progression
  The discrepancies in reported sulfotransferase expression in steatosis might result from differences in disease stages and from gender and age variations when the liver tissues were collected .

How does SULT1A2 expression differ between tumor tissues and adjacent normal tissues, and what are the implications?

Research has demonstrated significant differences in SULT1A2 expression between tumor tissues and adjacent normal tissues, particularly in bladder cancer:

• Use paired tumor and adjacent normal tissue samples from the same patient to control for individual variation

• Employ multiple detection methods (transcriptomic, protein-level, and functional assays)

• Correlate expression with clinical parameters and outcomes

• Investigate potential regulatory mechanisms driving differential expression
  These findings suggest that while SULT1A2 may act as an oncogene in bladder cancer, its high expression paradoxically correlates with better patient outcomes , highlighting the complex role of this enzyme in cancer biology.

What experimental models are most appropriate for studying SULT1A2 function?

Although the search results don't specifically address experimental models for SULT1A2 research, several approaches can be inferred based on the methodologies described:

• In vitro systems:

  • Recombinant protein expression: Human full-length SULT1A2 protein (295 amino acids) expressed in E. coli is available for enzymatic studies

  • Cell line models: Bladder cancer cell lines with varying levels of SULT1A2 expression can be used for functional studies

  • Primary cell cultures: Isolated from human tissues to study SULT1A2 in a more physiologically relevant context

• Ex vivo systems:

  • Human tissue samples: Analysis of SULT1A2 expression and activity in fresh or preserved human tissue samples

  • Precision-cut tissue slices: Maintaining the tissue architecture while allowing experimental manipulation

• In vivo models:

  • Genetically modified mice: With tissue-specific overexpression or knockout of SULT1A2

  • Xenograft models: Human cancer cells with modulated SULT1A2 expression implanted in immunodeficient mice

• Computational approaches:

  • Bioinformatic analysis of gene expression databases (TCGA, GEO)

  • Structural modeling and docking studies for substrate specificity

• Clinical samples:

  • Patient-derived tissue microarrays for correlation with clinical outcomes

  • Liquid biopsies for non-invasive biomarker studies
    For investigating specific research questions about SULT1A2, the most appropriate model system would depend on the particular aspect of SULT1A2 biology being studied (e.g., enzyme kinetics, regulation, role in disease, etc.).

How does SULT1A2 interact with phase I drug-metabolizing enzymes in xenobiotic metabolism?

• Sequential metabolism:

  • Phase I enzymes (primarily cytochrome P450s) typically introduce or expose functional groups on xenobiotics

  • SULT1A2, as a phase II enzyme, can then conjugate these metabolites with sulfate groups to increase water solubility

  • This sequential metabolism often represents a detoxification pathway

• Bioactivation pathways:

  • For certain compounds, particularly N-hydroxyarylamines, SULT1A2 can mediate metabolic activation to DNA binding products following initial phase I metabolism

  • This represents a bioactivation pathway that can increase genotoxicity and carcinogenicity

• Metabolic competition:

  • Metabolites generated by phase I enzymes may be substrates for multiple phase II enzymes

  • SULT1A2 may compete with other conjugating enzymes (e.g., UDP-glucuronosyltransferases, glutathione S-transferases) for the same substrates

• Enzyme induction/inhibition:

  • Xenobiotics that induce or inhibit phase I enzymes may indirectly affect SULT1A2 substrate availability

  • Some compounds may simultaneously affect both phase I and phase II enzymes, including SULT1A2 Methodologically, researchers studying these interactions should: