{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T03:31:52Z","timestamp":1790652712939,"version":"4.1.0"},"reference-count":22,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2021,1,4]],"date-time":"2021-01-04T00:00:00Z","timestamp":1609718400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes for Health Research","doi-asserted-by":"crossref","award":["93647"],"award-info":[{"award-number":["93647"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes for Health Research","doi-asserted-by":"crossref","award":["142329"],"award-info":[{"award-number":["142329"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,2,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Trimethoprim (TMP)-induced skin rash and liver injury are likely to involve the formation of reactive metabolites. Analogous to nevirapine-induced skin rash, 1 possible reactive metabolite is the sulfate conjugate of \u03b1-hydroxyTMP, a metabolite of TMP. We synthesized this sulfate and found that it reacts with proteins in vitro. We produced a TMP-antiserum and found covalent binding of TMP in the liver of TMP-treated rats. However, we found that \u03b1-hydroxyTMP is not a substrate for human sulfotransferases, and we did not detect covalent binding in the skin of TMP-treated rats. Although less reactive than the sulfate, \u03b1-hydroxyTMP was found to covalently bind to liver and skin proteins in vitro. Even though there was covalent binding to liver proteins, TMP did not cause liver injury in rats or in our impaired immune tolerance mouse model that has been able to unmask the ability of other drugs to cause immune-mediated liver injury. This is likely because there was much less covalent binding of TMP in the livers of TMP-treated mice than TMP-treated rats. It is possible that some patients have a sulfotransferase that can produce the reactive benzylic sulfate; however, \u03b1-hydroxyTMP, itself, has sufficient reactivity to covalently bind to proteins in the skin and may be responsible for TMP-induced skin rash. Interspecies and interindividual differences in TMP metabolism may be 1 factor that determines the risk of TMP-induced skin rash. This study provides important data required to understand the mechanism of TMP-induced skin rash and drug-induced skin rash in general.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaa182","type":"journal-article","created":{"date-parts":[[2020,12,12]],"date-time":"2020-12-12T20:10:12Z","timestamp":1607803812000},"page":"17-25","source":"Crossref","is-referenced-by-count":14,"title":["Investigating the Mechanism of Trimethoprim-Induced Skin Rash and Liver Injury"],"prefix":"10.1093","volume":"180","author":[{"given":"Yanshan","family":"Cao","sequence":"first","affiliation":[{"name":"Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto M5S3M2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahsan","family":"Bairam","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo Health Science Campus, Toledo, Ohio 43614"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Jee","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Toronto, Toronto M5S3M2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo Health Science Campus, Toledo, Ohio 43614"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Uetrecht","sequence":"additional","affiliation":[{"name":"Leslie Dan Faculty of Pharmacy, Faculty of Medicine, University of Toronto, Toronto M5S3M2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,1,4]]},"reference":[{"key":"2021022816091625400_kfaa182-B1","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.bcp.2018.03.005","article-title":"Sulfation of catecholamines and serotonin by SULT1A3 allozymes","volume":"151","author":"Bairam","year":"2018","journal-title":"Biochem. 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