SULT genetic polymorphisms: physiological, pharmacological and clinical implications

Kurogi, Katsuhisa; Rasool, Mohammed I.; Alherz, Fatemah A.; Daibani, Amal A. El; Bairam, Ahsan F.; Abunnaja, Maryam S.; Yasuda, Shin; Wilson, Lauren J.; Hui, Ying; Liu, Ming‐Cheh

doi:10.1080/17425255.2021.1940952

Cited by 30 publications

(26 citation statements)

References 215 publications

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“…The established EC50 in HL-ICOs was five-fold higher than those in PHHs and HepaRGs (which were comparable to the literature [ 19 ]). This difference could possibly be due to different media compositions (high levels of glutathione increase NAPQI conjugation) or increased activity in the alternative glucuronidation and sulfation pathways, as previously mentioned [ 45 , 46 , 47 ]. Exposure to the non-steroidal anti-inflammatory drug (NSAID) diclofenac showed that the sensitivity of one ICO donor was comparable to that of HepaRGs and PHHs [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing

et al. 2023

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Emerging advances in the field of in vitro toxicity testing attempt to meet the need for reliable human-based safety assessment in drug development. Intrahepatic cholangiocyte organoids (ICOs) are described as a donor-derived in vitro model for disease modelling and regenerative medicine. Here, we explored the potential of hepatocyte-like ICOs (HL-ICOs) in in vitro toxicity testing by exploring the expression and activity of genes involved in drug metabolism, a key determinant in drug-induced toxicity, and the exposure of HL-ICOs to well-known hepatotoxicants. The current state of drug metabolism in HL-ICOs showed levels comparable to those of PHHs and HepaRGs for CYP3A4; however, other enzymes, such as CYP2B6 and CYP2D6, were expressed at lower levels. Additionally, EC50 values were determined in HL-ICOs for acetaminophen (24.0–26.8 mM), diclofenac (475.5–>500 µM), perhexiline (9.7–>31.5 µM), troglitazone (23.1–90.8 µM), and valproic acid (>10 mM). Exposure to the hepatotoxicants showed EC50s in HL-ICOs comparable to those in PHHs and HepaRGs; however, for acetaminophen exposure, HL-ICOs were less sensitive. Further elucidation of enzyme and transporter activity in drug metabolism in HL-ICOs and exposure to a more extensive compound set are needed to accurately define the potential of HL-ICOs in in vitro toxicity testing.

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Section: Discussionmentioning

confidence: 99%

Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing

et al. 2023

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“…Only the SULT2 subfamily, including SULT2A1 and SUTL2B1, is associated with oxysterols sulfation in liver metabolism. [37] Since metabolic enzymes are regulated by drugs used by HCC patients, we also attempted to clarify the interventional factors using toxicotranscriptomics analysis and docking screen. We firstly demonstrated that APAP or THCL desensitized or sensitized HCC immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

SULT2B1-CS-DOCK2 axis regulates effector T-cell exhaustion in HCC microenvironment

Wang

et al. 2023

Hepatology

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Background and Aims: HCC is a malignant disease. Compared with tyrosine kinase inhibitors (the classical therapy), immune checkpoint inhibitors are more effective in the treatment of HCC, despite their limited efficacy. Among these restricted factors, exhaustion of tumor-infiltrated lymphocytes, especially CD8+ T cells, is a core event. We aimed to determine the key factors contributing to CD8+ T-cell infiltration in HCC and investigate the underlying mechanisms. Approach and Results: Using machine learning and multiplex immunohistochemistry analysis, we showed that dedicator of cytokinesis protein 2 (DOCK2) was a potential indicator of infiltrated CD8+ T cells in HCC. Using RNA sequencing, flow cytometry analysis, and mouse HCC models, we demonstrated that DOCK2 inactivation accounted for infiltrated CD8+ T-cell exhaustion in tumors. Using quasi-targeted metabolomics, mass spectrum, and mass cytometry by time of flight analysis, we found that cholesterol sulfate synthesized by sulfotransferase 2B1 in tumor cells suppressed DOCK2 enzymatic activity of T cells. Through virtual screening, molecular docking simulation, and experiments validation, we demonstrated that tolazamide reversed DOCK2 inactivation-mediated CD8+ T-cell exhaustion and enhanced anti–programmed death-ligand 1 antibody+apatinib immunotherapeutic effects on HCC. Conclusions: This study indicates that DOCK2 controls CD8+ T-cell infiltration in HCC, and cholesterol sulfate synthesized by sulfotransferase 2B1 in tumor cells promotes effector T-cell exhaustion. The findings suggest that the usage of conventional drugs affects immunotherapy efficacy in HCC patients.

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“…Another study indicates that acetaminophen and salicylate derivatives could decrease the expression of AMFR protein through p38 MAPK activation, resulting in the inhibition of CYP3A protein degradation and a subsequent increase in enzymatic activity [ 82 ]. In addition, the detoxification-related enzyme sulfotransferase 1A3 (SULT1A3) is found to be degraded much more rapidly by a ubiquitin–proteasome system-dependent process in case of genetic variation [ 83 ].…”

Section: Protein Degradation-mediated Aberrant Drug Transport and Met...mentioning

confidence: 99%

Protein degradation: expanding the toolbox to restrain cancer drug resistance

Hui

Jiang

et al. 2023

J Hematol Oncol

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Despite significant progress in clinical management, drug resistance remains a major obstacle. Recent research based on protein degradation to restrain drug resistance has attracted wide attention, and several therapeutic strategies such as inhibition of proteasome with bortezomib and proteolysis-targeting chimeric have been developed. Compared with intervention at the transcriptional level, targeting the degradation process seems to be a more rapid and direct strategy. Proteasomal proteolysis and lysosomal proteolysis are the most critical quality control systems responsible for the degradation of proteins or organelles. Although proteasomal and lysosomal inhibitors (e.g., bortezomib and chloroquine) have achieved certain improvements in some clinical application scenarios, their routine application in practice is still a long way off, which is due to the lack of precise targeting capabilities and inevitable side effects. In-depth studies on the regulatory mechanism of critical protein degradation regulators, including E3 ubiquitin ligases, deubiquitylating enzymes (DUBs), and chaperones, are expected to provide precise clues for developing targeting strategies and reducing side effects. Here, we discuss the underlying mechanisms of protein degradation in regulating drug efflux, drug metabolism, DNA repair, drug target alteration, downstream bypass signaling, sustaining of stemness, and tumor microenvironment remodeling to delineate the functional roles of protein degradation in drug resistance. We also highlight specific E3 ligases, DUBs, and chaperones, discussing possible strategies modulating protein degradation to target cancer drug resistance. A systematic summary of the molecular basis by which protein degradation regulates tumor drug resistance will help facilitate the development of appropriate clinical strategies.

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SULT genetic polymorphisms: physiological, pharmacological and clinical implications

Cited by 30 publications

References 215 publications

Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing

Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing

SULT2B1-CS-DOCK2 axis regulates effector T-cell exhaustion in HCC microenvironment

Protein degradation: expanding the toolbox to restrain cancer drug resistance

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