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2'-Deoxythymidine Adducts from the Anti-HIV Drug Nevirapine
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 produce...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269667/ https://www.ncbi.nlm.nih.gov/pubmed/23624649 http://dx.doi.org/10.3390/molecules18054955 |
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author | Antunes, Alexandra M. M. Wolf, Benjamin Oliveira, M. Conceição Beland, Frederick A. Marques, M. Matilde |
author_facet | Antunes, Alexandra M. M. Wolf, Benjamin Oliveira, M. Conceição Beland, Frederick A. Marques, M. Matilde |
author_sort | Antunes, Alexandra M. M. |
collection | PubMed |
description | 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’-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. |
format | Online Article Text |
id | pubmed-6269667 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-62696672018-12-14 2'-Deoxythymidine Adducts from the Anti-HIV Drug Nevirapine Antunes, Alexandra M. M. Wolf, Benjamin Oliveira, M. Conceição Beland, Frederick A. Marques, M. Matilde Molecules Article 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’-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. MDPI 2013-04-26 /pmc/articles/PMC6269667/ /pubmed/23624649 http://dx.doi.org/10.3390/molecules18054955 Text en © 2013 by the authors; licensee MDPI, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0/ This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/). |
spellingShingle | Article Antunes, Alexandra M. M. Wolf, Benjamin Oliveira, M. Conceição Beland, Frederick A. Marques, M. Matilde 2'-Deoxythymidine Adducts from the Anti-HIV Drug Nevirapine |
title | 2'-Deoxythymidine Adducts from the Anti-HIV Drug Nevirapine |
title_full | 2'-Deoxythymidine Adducts from the Anti-HIV Drug Nevirapine |
title_fullStr | 2'-Deoxythymidine Adducts from the Anti-HIV Drug Nevirapine |
title_full_unstemmed | 2'-Deoxythymidine Adducts from the Anti-HIV Drug Nevirapine |
title_short | 2'-Deoxythymidine Adducts from the Anti-HIV Drug Nevirapine |
title_sort | 2'-deoxythymidine adducts from the anti-hiv drug nevirapine |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269667/ https://www.ncbi.nlm.nih.gov/pubmed/23624649 http://dx.doi.org/10.3390/molecules18054955 |
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