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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| Format: | Article |
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MDPI AG
2013-04-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/18/5/4955 |
| _version_ | 1798043857094443008 |
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| author | M. Matilde Marques Frederick A. Beland M. Conceição Oliveira Benjamin Wolf Alexandra M. M. Antunes |
| author_facet | M. Matilde Marques Frederick A. Beland M. Conceição Oliveira Benjamin Wolf Alexandra M. M. Antunes |
| author_sort | M. Matilde Marques |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-11T22:54:55Z |
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| id | doaj.art-e433db39f6a14f459bcbf2869306662a |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-04-11T22:54:55Z |
| publishDate | 2013-04-01 |
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| series | Molecules |
| spelling | doaj.art-e433db39f6a14f459bcbf2869306662a2022-12-22T03:58:28ZengMDPI 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 |
| 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 |
| 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 | 2 039 deoxythymidine adducts from the anti hiv drug nevirapine |
| 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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