{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:31:39Z","timestamp":1760243499962,"version":"build-2065373602"},"reference-count":45,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2013,4,26]],"date-time":"2013-04-26T00:00:00Z","timestamp":1366934400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used against HIV-1. Currently, NVP is the most widely used anti-HIV drug in developing countries, both in combination therapy and to prevent mother-to-child transmission of HIV. Despite its efficacy against HIV, NVP produces a variety of toxic responses, including hepatotoxicity and skin rash. It is also associated with increased incidences of hepatoneoplasias in rodents. In addition, epidemiological data suggest that NNRTI use is a risk factor for non-AIDS-defining cancers in HIV-positive patients. Current evidence supports the involvement of metabolic activation to reactive electrophiles in NVP toxicity. NVP metabolism includes oxidation to 12-hydroxy-NVP; subsequent Phase II sulfonation produces an electrophilic metabolite, 12-sulfoxy-NVP, capable of reacting with DNA to yield covalent adducts. Since 2\u2019-deoxythymidine (dT) adducts from several alkylating agents are regarded as having significant mutagenic\/carcinogenic potential, we investigated the formation of NVP-dT adducts under biomimetic conditions. Toward this goal,  we initially prepared and characterized synthetic NVP-dT adduct standards using a  palladium-mediated Buchwald-Hartwig coupling strategy. The synthetic standards enabled the identification, by LC-ESI-MS, of 12-(2'-deoxythymidin-N3-yl)-nevirapine (N3-NVP-dT) in the enzymatic hydrolysate of salmon testis DNA reacted with 12-mesyloxy-NVP,  a synthetic surrogate for 12-sulfoxy-NVP. N3-NVP-dT, a potentially cytotoxic and mutagenic DNA lesion, was also the only dT-specific adduct detected upon reaction of dT with 12-mesyloxy-NVP. Our data suggest that N3-NVP-dT may be formed in vivo and play a role in the hepatotoxicity and\/or putative hepatocarcinogenicity of NVP.<\/jats:p>","DOI":"10.3390\/molecules18054955","type":"journal-article","created":{"date-parts":[[2013,4,26]],"date-time":"2013-04-26T11:27:28Z","timestamp":1366975648000},"page":"4955-4971","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["2'-Deoxythymidine Adducts from the Anti-HIV Drug Nevirapine"],"prefix":"10.3390","volume":"18","author":[{"given":"Alexandra","family":"Antunes","sequence":"first","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Instituto Superior T\u00e9cnico, Universidade T\u00e9cnica de Lisboa,  Av. Rovisco Pais, 1049-001 Lisboa, Portugal"}]},{"given":"Benjamin","family":"Wolf","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Instituto Superior T\u00e9cnico, Universidade T\u00e9cnica de Lisboa,  Av. Rovisco Pais, 1049-001 Lisboa, Portugal"}]},{"given":"M.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Instituto Superior T\u00e9cnico, Universidade T\u00e9cnica de Lisboa,  Av. Rovisco Pais, 1049-001 Lisboa, Portugal"}]},{"given":"Frederick","family":"Beland","sequence":"additional","affiliation":[{"name":"Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson,  AR 72079, USA"}]},{"given":"M.","family":"Marques","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Instituto Superior T\u00e9cnico, Universidade T\u00e9cnica de Lisboa,  Av. Rovisco Pais, 1049-001 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2013,4,26]]},"reference":[{"key":"ref_1","unstructured":"Available online:http:\/\/www.who.int\/rpc\/guidelines\/hiv_aids\/en\/index.html."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1200\/JCO.2008.19.6626","article-title":"Highly active antiretroviral therapy and the incidence of non-AIDS-defining cancers in people with HIV infection","volume":"27","author":"Powles","year":"2009","journal-title":"J. Clin. 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