乐胖代购免代理版

{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T13:07:19Z","timestamp":1740143239720,"version":"3.37.3"},"update-to":[{"updated":{"date-parts":[[2021,8,17]],"date-time":"2021-08-17T00:00:00Z","timestamp":1629158400000},"DOI":"10.1371\/journal.pcbi.1009110","type":"new_version","source":"publisher","label":"New version"}],"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2021,8,5]],"date-time":"2021-08-05T00:00:00Z","timestamp":1628121600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"NSERC","doi-asserted-by":"crossref","award":["Discovery Program"],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"crossref"}]},{"name":"M3 CREATE"},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["757922"],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"Ethanol is one of the most widely used recreational substances in the world and due to its ubiquitous use, ethanol abuse has been the cause of over 3.3 million deaths each year. In addition to its effects, ethanol\u2019s primary metabolite, acetaldehyde, is a carcinogen that can cause symptoms of facial flushing, headaches, and nausea. How strongly ethanol or acetaldehyde affects an individual depends highly on the genetic polymorphisms of certain genes. In particular, the genetic polymorphisms of mitochondrial aldehyde dehydrogenase, ALDH2, play a large role in the metabolism of acetaldehyde. Thus, it is important to characterize how genetic variations can lead to different exposures and responses to ethanol and acetaldehyde. While the pharmacokinetics of ethanol metabolism through alcohol dehydrogenase have been thoroughly explored in previous studies, in this paper, we combined a base physiologically-based pharmacokinetic (PBPK) model with a whole-body genome-scale model (WBM) to gain further insight into the effect of other less explored processes and genetic variations on ethanol metabolism. This combined model was fit to clinical data and used to show the effect of alcohol concentrations, organ damage, ALDH2 enzyme polymorphisms, and ALDH2-inhibiting drug disulfiram on ethanol and acetaldehyde exposure. Through estimating the reaction rates of auxiliary processes with dynamic Flux Balance Analysis, The PBPK-WBM was able to navigate around a lack of kinetic constants traditionally associated with PK modelling and demonstrate the compensatory effects of the body in response to decreased liver enzyme expression. Additionally, the model demonstrated that acetaldehyde exposure increased with higher dosages of disulfiram and decreased ALDH2 efficiency, and that moderate consumption rates of ethanol could lead to unexpected accumulations in acetaldehyde. This modelling framework combines the comprehensive steady-state analyses from genome-scale models with the dynamics of traditional PK models to create a highly personalized form of PBPK modelling that can push the boundaries of precision medicine.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1009110","type":"journal-article","created":{"date-parts":[[2021,8,5]],"date-time":"2021-08-05T18:08:41Z","timestamp":1628186921000},"page":"e1009110","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["Integration of a physiologically-based pharmacokinetic model with a whole-body, organ-resolved genome-scale model for characterization of ethanol and acetaldehyde metabolism"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3492-3981","authenticated-orcid":true,"given":"Leo","family":"Zhu","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5401-1440","authenticated-orcid":true,"given":"William","family":"Pei","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8071-7110","authenticated-orcid":true,"given":"Ines","family":"Thiele","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1270-9063","authenticated-orcid":true,"given":"Radhakrishnan","family":"Mahadevan","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2021,8,5]]},"reference":[{"volume-title":"Global status report on alcohol and health 2018","year":"2018","author":"World Health Organization (WHO)","key":"pcbi.1009110.ref001"},{"issue":"1\u20133","key":"pcbi.1009110.ref002","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.forsciint.2010.02.021","article-title":"Evidence-based survey of the elimination rates of ethanol from blood with applications in forensic casework","volume":"200","author":"AW Jones","year":"2010","journal-title":"Forensic Sci Int"},{"key":"pcbi.1009110.ref003","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/B978-0-12-800213-1.00035-3","volume-title":"Neuropathology of Drug Addictions and Substance Misuse","author":"R Rajendram","year":"2016"},{"key":"pcbi.1009110.ref004","doi-asserted-by":"crossref","first-page":"1543809","DOI":"10.1155\/2016\/1543809","article-title":"Lipids and Oxidative Stress Associated with Ethanol-Induced Neurological Damage","volume":"2016","author":"JA Hern\u00e1ndez","year":"2016","journal-title":"Oxid Med Cell Longev"},{"issue":"12","key":"pcbi.1009110.ref005","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1002\/iub.1569","article-title":"Nonoxidative ethanol metabolism in humans\u2014from biomarkers to bioactive lipids","volume":"68","author":"C Heier","year":"2016","journal-title":"IUBMB Life"},{"issue":"4","key":"pcbi.1009110.ref006","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/j.cld.2012.08.002","article-title":"Alcohol Metabolism","volume":"16","author":"A. 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