Drug Metabolism Reviews最新文献

{"title":"Effects of xenobiotics on CYP1 enzyme-mediated biotransformation and bioactivation of estradiol.","authors":"Xu Mao,&nbsp;Hui Li,&nbsp;Jiang Zheng","doi":"10.1080/03602532.2023.2177671","DOIUrl":"https://doi.org/10.1080/03602532.2023.2177671","url":null,"abstract":"<p><p>Endogenous estradiol (E2) exerts diverse physiological and pharmacological activities, commonly used for hormone replacement therapy. However, prolonged and excessive exposure to E2 potentially increases estrogenic cancer risk. Reportedly, CYP1 enzyme-mediated biotransformation of E2 is largely concerned with its balance between detoxification and carcinogenic pathways. Among the three key CYP1 enzymes (CYP1A1, CYP1A2, and CYP1B1), CYP1A1 and CYP1A2 mainly catalyze the formation of nontoxic 2-hydroxyestradiol (2-OH-E2), while CYP1B1 specifically catalyzes the formation of genotoxic 4-hydroxyestradiol (4-OH-E2). 4-OH-E2 can be further metabolized to electrophilic quinone intermediates accompanied by the generation of reactive oxygen species (ROS), triggering DNA damage. Since abnormal alterations in CYP1 activities can greatly affect the bioactivation process of E2, regulatory effects of xenobiotics on CYP1s are essential for E2-associated cancer development. To date, thousands of natural and synthetic compounds have been found to show potential inhibition and/or induction actions on the three CYP1 members. Generally, these chemicals share similar planar polycyclic skeletons, the structural motifs and substituent groups of which are important for their inhibitory/inductive efficiency and selectivity toward CYP1 enzymes. This review comprehensively summarizes these known inhibitors and/or inductors of E2-metabolizing CYP1s based on chemical categories and discusses their structure-activity relationships, which would contribute to better understanding of the correlation between xenobiotic-regulated CYP1 activities and estrogenic cancer susceptibility.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"55 1-2","pages":"1-49"},"PeriodicalIF":5.9,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9501095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular mechanisms of hepatotoxicity induced by compounds occurring in Evodiae Fructus.","authors":"Caiqin Yan,&nbsp;Ting Peng,&nbsp;Tingting Zhang,&nbsp;Yuan Wang,&nbsp;Na Li,&nbsp;Kai Wang,&nbsp;Xijuan Jiang","doi":"10.1080/03602532.2023.2180027","DOIUrl":"https://doi.org/10.1080/03602532.2023.2180027","url":null,"abstract":"Abstract Evodiae Fructus (EF) is a common herbal medicine with thousands of years of medicinal history in China, which has been demonstrated with many promising pharmacological effects on cancer, cardiovascular diseases and Alzheimer’s disease. However, there have been increasing reports of hepatotoxicity associated with EF consumption. Unfortunately, in a long term, many implicit constituents of EF as well as their toxic mechanisms remain poorly understood. Recently, metabolic activation of hepatotoxic compounds of EF to generate reactive metabolites (RMs) has been implicated. Herein, we capture metabolic reactions relevant to hepatotoxicity of these compounds. Initially, catalyzed by the hepatic cytochrome P450 enzymes (CYP450s), the hepatotoxic compounds of EF are oxidized to generate RMs. Subsequently, the highly electrophilic RMs could react with nucleophilic groups contained in biomolecules, such as hepatic proteins, enzymes, and nucleic acids to form conjugates and/or adducts, leading to a sequence of toxicological consequences. In addition, currently proposed biological pathogenesis, including oxidative stress, mitochondrial damage and dysfunction, endoplasmic reticulum (ER) stress, hepatic metabolism disorder, and cell apoptosis are represented. In short, this review updates the knowledge on the pathways of metabolic activation of seven hepatotoxic compounds of EF and provides considerable insights into the relevance of proposed molecular hepatotoxicity mechanisms from a biochemical standpoint, for the purpose of providing a theoretical guideline for the rational application of EF in clinics.","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"55 1-2","pages":"75-93"},"PeriodicalIF":5.9,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9554140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolism of the areca alkaloids - toxic and psychoactive constituents of the areca (betel) nut.","authors":"Alan L Myers","doi":"10.1080/03602532.2022.2075010","DOIUrl":"https://doi.org/10.1080/03602532.2022.2075010","url":null,"abstract":"<p><p>Areca nut (AN) is consumed by millions of people for its therapeutic and psychoactive effects, making it one of the most widely self-administered psychoactive substances in the world. Even so, AN use/abuse is associated with myriad oral and systemic side effects, affecting most organ systems in the body. Alkaloids abundant in the nut (e.g. arecoline, arecaidine, guvacoline, and guvacine), collectively called the areca alkaloids, are presumably responsible for the major pharmacological effects experienced by users, with arecoline being the most abundant alkaloid with notable toxicological properties. However, the mechanisms of arecoline and other areca alkaloid elimination in humans remain poorly documented. Therefore, the purpose of this review is to provide an in-depth review of areca alkaloid pharmacokinetics (PK) in biological systems, and discuss mechanisms of metabolism by presenting information found in the literature. Also, the toxicological relevance of the known and purported metabolic steps will be reviewed. In brief, several areca alkaloids contain a labile methyl ester group and are susceptible to hydrolysis, although the human esterase responsible remains presumptive. Other notable mechanisms include <i>N</i>-oxidation, glutathionylation, nitrosamine conversion, and carbon-carbon double-bond reduction. These metabolic conversions result in toxic and sometimes less-toxic derivatives. Arecoline and arecaidine undergo extensive metabolism while far less is known about guvacine and guvacoline. Metabolism information may help predict drug interactions with human pharmaceuticals with overlapping elimination pathways. Altogether, this review provides a first-of-its-kind comprehensive analysis of AN alkaloid metabolism, adds perspective on new mechanisms of metabolism, and highlights the need for future metabolism work in the field.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"54 4","pages":"343-360"},"PeriodicalIF":5.9,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10362414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cutting-edge strategies and critical advancements in characterization and quantification of metabolites concerning translational metabolomics.","authors":"Megha Sajakumar Pillai,&nbsp;Sree Teja Paritala,&nbsp;Ravi P Shah,&nbsp;Nitish Sharma,&nbsp;Pinaki Sengupta","doi":"10.1080/03602532.2022.2125987","DOIUrl":"https://doi.org/10.1080/03602532.2022.2125987","url":null,"abstract":"<p><p>Despite remarkable progress in drug discovery strategies, significant challenges are still remaining in translating new insights into clinical applications. Scientists are devising creative approaches to bridge the gap between scientific and translational research. Metabolomics is a unique field among other omics techniques for identifying novel metabolites and biomarkers. Fortunately, characterization and quantification of metabolites are becoming faster due to the progress in the field of orthogonal analytical techniques. This review detailed the advancement in the progress of sample preparation, and data processing techniques including data mining tools, database, and their quality control (QC). Advances in data processing tools make it easier to acquire unbiased data that includes a diverse set of metabolites. In addition, novel breakthroughs including, miniaturization as well as their integration with other devices, metabolite array technology, and crystalline sponge-based method have led to faster, more efficient, cost-effective, and holistic metabolomic analysis. The use of cutting-edge techniques to identify the human metabolite, including biomarkers has proven to be advantageous in terms of early disease identification, tracking the progression of illness, and possibility of personalized treatments. This review addressed the constraints of current metabolomics research, which are impeding the facilitation of translation of research from bench to bedside. Nevertheless, the possible way out from such constraints and future direction of translational metabolomics has been conferred.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"54 4","pages":"401-426"},"PeriodicalIF":5.9,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10364124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A transcriptional regulatory network of HNF4α and HNF1α involved in human diseases and drug metabolism.","authors":"Jianxin Yang,&nbsp;Xue Bai,&nbsp;Guiqin Liu,&nbsp;Xiangyang Li","doi":"10.1080/03602532.2022.2103146","DOIUrl":"https://doi.org/10.1080/03602532.2022.2103146","url":null,"abstract":"<p><p>HNF4α and HNF1α are core transcription factors involved in the development and progression of a variety of human diseases and drug metabolism. They play critical roles in maintaining the normal growth and function of multiple organs, mainly the liver, and in the metabolism of endogenous and exogenous substances. The twelve isoforms of HNF4α may exhibit different physiological functions, and HNF4α and HNF1α show varying or even opposing effects in different types of diseases, particularly cancer. Additionally, the regulation of CYP450, phase II drug-metabolizing enzymes, and drug transporters is affected by several factors. This article aims to review the role of HNF4α and HNF1α in human diseases and drug metabolism, including their structures and physiological functions, affected diseases, regulated drug metabolism genes, influencing factors, and related mechanisms. We also propose a transcriptional regulatory network of HNF4α and HNF1α that regulates the expression of target genes related to disease and drug metabolism.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"54 4","pages":"361-385"},"PeriodicalIF":5.9,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10485678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aldehyde oxidase mediated drug metabolism: an underpredicted obstacle in drug discovery and development.","authors":"Siva Nageswara Rao Gajula,&nbsp;Tanaaz Navin Nathani,&nbsp;Rashmi Madhukar Patil,&nbsp;Sasikala Talari,&nbsp;Rajesh Sonti","doi":"10.1080/03602532.2022.2144879","DOIUrl":"https://doi.org/10.1080/03602532.2022.2144879","url":null,"abstract":"<p><p>Aldehyde oxidase (AO) has garnered curiosity as a non-CYP metabolizing enzyme in drug development due to unexpected consequences such as toxic metabolite generation and high metabolic clearance resulting in the clinical failure of new drugs. Therefore, poor AO mediated clearance prediction in preclinical nonhuman species remains a significant obstacle in developing novel drugs. Various isoforms of AO, such as <i>AOX1, AOX3, AOX3L1</i>, and <i>AOX4</i> exist across species, and different AO activity among humans influences the AO mediated drug metabolism. Therefore, carefully considering the unique challenges is essential in developing successful AO substrate drugs. The <i>in vitro</i> to <i>in vivo</i> extrapolation underpredicts AO mediated drug clearance due to the lack of reliable representative animal models, substrate-specific activity, and the discrepancy between absolute concentration and activity. An <i>in vitro</i> tool to extrapolate <i>in vivo</i> clearance using a yard-stick approach is provided to address the underprediction of AO mediated drug clearance. This approach uses a range of well-known AO drug substrates as calibrators for qualitative scaling new drugs into low, medium, or high clearance category drugs. So far, <i>in vivo</i> investigations on chimeric mice with humanized livers (humanized mice) have predicted AO mediated metabolism to the best extent. This review addresses the critical aspects of the drug discovery stage for AO metabolism studies, challenges faced in drug development, approaches to tackle AO mediated drug clearance's underprediction, and strategies to decrease the AO metabolism of drugs.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"54 4","pages":"427-448"},"PeriodicalIF":5.9,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10732703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting endothelial cell metabolism in cancerous microenvironment: a new approach for anti-angiogenic therapy.","authors":"Parisa Mohammadi,&nbsp;Reza Yarani,&nbsp;Azam Rahimpour,&nbsp;Fatemeh Ranjbarnejad,&nbsp;Joana Mendes Lopes de Melo,&nbsp;Kamran Mansouri","doi":"10.1080/03602532.2022.2116033","DOIUrl":"https://doi.org/10.1080/03602532.2022.2116033","url":null,"abstract":"<p><p>Anti-angiogenic therapy is a practical approach to managing diseases with increased angiogenesis, such as cancer, maculopathies, and retinopathies. Considering the fundamental gaps in the knowledge of the vital pathways involved in angiogenesis and its inhibition and the insufficient efficiency of existing angiogenesis inhibitors, there is an increasing focus on the emergence of new therapeutic strategies aimed at inhibiting pathological angiogenesis. Angiogenesis is forming a new vascular network from existing vessels; endothelial cells (ECs), vascular lining cells, are the main actors of angiogenesis in physiological or pathological conditions. Switching from a quiescent state to a highly migratory and proliferative state during new vessel formation called \"angiogenic switch\" is driven by a \"metabolic switch\" in ECs, angiogenic growth factors, and other signals. As the characteristics of ECs change by altering the surrounding environment, they appear to have a different metabolism in a tumor microenvironment (TME). Therefore, pathological angiogenesis can be inhibited by targeting metabolic pathways. In the current review, we aim to discuss the EC metabolic pathways under normal and TME conditions to verify the suitability of targeting them with novel therapies.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"54 4","pages":"386-400"},"PeriodicalIF":5.9,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10714297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioactivation and reactivity research advances - 2021 year in review.","authors":"Klarissa D Jackson,&nbsp;Upendra A Argikar,&nbsp;Sungjoon Cho,&nbsp;Rachel D Crouch,&nbsp;James P Driscoll,&nbsp;Carley J S Heck,&nbsp;Lloyd King,&nbsp;Hlaing Holly Maw,&nbsp;Grover P Miller,&nbsp;Herana Kamal Seneviratne,&nbsp;Shuai Wang,&nbsp;Cong Wei,&nbsp;Donglu Zhang,&nbsp;S Cyrus Khojasteh","doi":"10.1080/03602532.2022.2097254","DOIUrl":"https://doi.org/10.1080/03602532.2022.2097254","url":null,"abstract":"<p><p>This year's review on bioactivation and reactivity began as a part of the annual review on biotransformation and bioactivation led by Cyrus Khojasteh (see references). Increased contributions from experts in the field led to the development of a stand alone edition for the first time this year focused specifically on bioactivation and reactivity. Our objective for this review is to highlight and share articles which we deem influential and significant regarding the development of covalent inhibitors, mechanisms of reactive metabolite formation, enzyme inactivation, and drug safety. Based on the selected articles, we created two sections: (1) reactivity and enzyme inactivation, and (2) bioactivation mechanisms and safety (Table 1). Several biotransformation experts have contributed to this effort from academic and industry settings.[Table: see text].</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"54 3","pages":"246-281"},"PeriodicalIF":5.9,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/4f/64/nihms-1898966.PMC10282953.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9756543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetics in drug disposition & drug therapy: symposium report of the 24^th North American meeting of the International Society for the Study of Xenobiotics (ISSX).","authors":"Benjamin J Maldonato,&nbsp;Ana G Vergara,&nbsp;Jaydeep Yadav,&nbsp;Sarah M Glass,&nbsp;Erickson M Paragas,&nbsp;Dongying Li,&nbsp;Philip Lazarus,&nbsp;Joseph L McClay,&nbsp;Baitang Ning,&nbsp;Ann K Daly,&nbsp;Laura E Russell","doi":"10.1080/03602532.2022.2101662","DOIUrl":"https://doi.org/10.1080/03602532.2022.2101662","url":null,"abstract":"<p><p>The 24th North American International Society for the Study of Xenobiotics (ISSX) meeting, held virtually from September 13 to 17, 2021, embraced the theme of \"Broadening Our Horizons.\" This reinforces a key mission of ISSX: striving to share innovative science related to drug discovery and development. Session speakers and the ISSX New Investigators Group, which supports the scientific and professional development of student and early career ISSX members, elected to highlight the scientific content presented during the captivating session titled, \"Epigenetics in Drug Disposition & Drug Therapy.\" The impact genetic variation has on drug response is well established; however, this session underscored the importance of investigating the role of epigenetics in drug disposition and drug discovery. Session speakers, Drs. Ning, McClay, and Lazarus, detailed mechanisms by which epigenetic players including long non-coding RNA (lncRNAs), microRNA (miRNAs), DNA methylation, and histone acetylation can alter the expression of genes involved in pharmacokinetics, pharmacodynamics, and toxicity. Dr. Ning detailed current knowledge about miRNAs and lncRNAs and the mechanisms by which they can affect the expression of drug metabolizing enzymes (DMEs) and nuclear receptors. Dr. Lazarus discussed the potential role of miRNAs on UDP-glucuronosyltransferase (UGT) expression and activity. Dr. McClay provided evidence that aging alters methylation and acetylation of DMEs in the liver, affecting gene expression and activity. These topics, compiled by the symposium organizers, presenters, and the ISSX New Investigators Group, are herein discussed, along with exciting future perspectives for epigenetics in drug disposition and drug discovery research.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"54 3","pages":"318-330"},"PeriodicalIF":5.9,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9970013/pdf/nihms-1865806.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10417662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biotransformation novel advances - 2021 year in review.","authors":"S Cyrus Khojasteh,&nbsp;Upendra A Argikar,&nbsp;Sungjoon Cho,&nbsp;Rachel Crouch,&nbsp;Carley J S Heck,&nbsp;Kevin M Johnson,&nbsp;Amit S Kalgutkar,&nbsp;Lloyd King,&nbsp;Hlaing Holly Maw,&nbsp;Herana Kamal Seneviratne,&nbsp;Shuai Wang,&nbsp;Cong Wei,&nbsp;Donglu Zhang,&nbsp;Klarissa D Jackson","doi":"10.1080/03602532.2022.2097253","DOIUrl":"https://doi.org/10.1080/03602532.2022.2097253","url":null,"abstract":"<p><p>Biotransformation field is constantly evolving with new molecular structures and discoveries of metabolic pathways that impact efficacy and safety. Recent review by Kramlinger et al. (2022) nicely captures the future (and the past) of highly impactful science of biotransformation (see the first article). Based on the selected articles, this review was categorized into three sections: (1) new modalities biotransformation, (2) drug discovery biotransformation, and (3) drug development biotransformation (Table 1).</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":"54 3","pages":"207-245"},"PeriodicalIF":5.9,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/4f/e1/nihms-1898969.PMC10249656.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9597439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}