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...
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doaj-e433db39f6a14f459bcbf2869306662a2020-11-25T00:17:45ZengMDPI AGMolecules1420-30492013-04-011854955497110.3390/molecules180549552'-Deoxythymidine Adducts from the Anti-HIV Drug NevirapineM. Matilde MarquesFrederick A. BelandM. Conceição OliveiraBenjamin WolfAlexandra M. M. AntunesNevirapine (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.http://www.mdpi.com/1420-3049/18/5/4955nevirapinenon-nucleoside reverse transcriptase inhibitorcarcinogenicityDNA adductspalladium catalysis |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
M. Matilde Marques Frederick A. Beland M. Conceição Oliveira Benjamin Wolf Alexandra M. M. Antunes |
spellingShingle |
M. Matilde Marques Frederick A. Beland M. Conceição Oliveira Benjamin Wolf Alexandra M. M. Antunes 2'-Deoxythymidine Adducts from the Anti-HIV Drug Nevirapine Molecules nevirapine non-nucleoside reverse transcriptase inhibitor carcinogenicity DNA adducts palladium catalysis |
author_facet |
M. Matilde Marques Frederick A. Beland M. Conceição Oliveira Benjamin Wolf Alexandra M. M. Antunes |
author_sort |
M. Matilde Marques |
title |
2'-Deoxythymidine Adducts from the Anti-HIV Drug Nevirapine |
title_short |
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_sort |
2'-deoxythymidine adducts from the anti-hiv drug nevirapine |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2013-04-01 |
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. |
topic |
nevirapine non-nucleoside reverse transcriptase inhibitor carcinogenicity DNA adducts palladium catalysis |
url |
http://www.mdpi.com/1420-3049/18/5/4955 |
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