دورية أكاديمية
أعرض في EDS

Quantitative Chemical Proteomic Profiling of the in Vivo Targets of Reactive Drug Metabolites.

التفاصيل البيبلوغرافية
العنوان: Quantitative Chemical Proteomic Profiling of the in Vivo Targets of Reactive Drug Metabolites.
المؤلفون: Whitby LR; The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute , 10550 N. Torrey Pines Rd., La Jolla, California 92307, United States., Obach RS; Pfizer Worldwide Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States., Simon GM; Vividion Therapeutics , 3033 Science Park Rd Suite D, San Diego, California 92121, United States., Hayward MM; Pfizer Worldwide Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States., Cravatt BF; The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute , 10550 N. Torrey Pines Rd., La Jolla, California 92307, United States.
المصدر: ACS chemical biology [ACS Chem Biol] 2017 Aug 18; Vol. 12 (8), pp. 2040-2050. Date of Electronic Publication: 2017 Jun 21.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 101282906 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1554-8937 (Electronic) Linking ISSN: 15548929 NLM ISO Abbreviation: ACS Chem Biol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, D.C. : American Chemical Society, c2006-
مواضيع طبية MeSH: Chemical and Drug Induced Liver Injury* , Drug Delivery Systems* , Proteogenomics*, Acetaminophen/*toxicity , Hepatocytes/*drug effects, Acetaminophen/chemistry ; Acetaminophen/pharmacology ; Animals ; Liver/injuries ; Mice ; Molecular Structure
مستخلص: Idiosyncratic liver toxicity represents an important problem in drug research and pharmacotherapy. Reactive drug metabolites that modify proteins are thought to be a principal factor in drug-induced liver injury. Here, we describe a quantitative chemical proteomic method to identify the targets of reactive drug metabolites in vivo. Treating mice with clickable analogues of four representative hepatotoxic drugs, we demonstrate extensive covalent binding that is confined primarily to the liver. Each drug exhibited a distinct target profile that, in certain cases, showed strong enrichment for specific metabolic pathways (e.g., lipid/sterol pathways for troglitazone). Site-specific proteomics revealed that acetaminophen reacts with high stoichiometry with several conserved, functional (seleno)cysteine residues throughout the liver proteome. Our findings thus provide an advanced experimental framework to characterize the proteomic reactivity of drug metabolites in vivo, revealing target profiles that may help to explain mechanisms and identify risk factors for drug-induced liver injury.
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معلومات مُعتمدة: R01 CA087660 United States CA NCI NIH HHS; R37 CA087660 United States CA NCI NIH HHS
المشرفين على المادة: 362O9ITL9D (Acetaminophen)
تواريخ الأحداث: Date Created: 20170622 Date Completed: 20180220 Latest Revision: 20181113
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC5626524
DOI: 10.1021/acschembio.7b00346
PMID: 28636309
قاعدة البيانات: MEDLINE
الوصف
تدمد:1554-8937
DOI:10.1021/acschembio.7b00346