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Molecules 2013, 18(5), 4955-4971; doi:10.3390/molecules18054955

2'-Deoxythymidine Adducts from the Anti-HIV Drug Nevirapine

1,* , 1, 1, 2 and 1,*
Received: 12 March 2013 / Revised: 18 April 2013 / Accepted: 19 April 2013 / Published: 26 April 2013
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Abstract: 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.
Keywords: nevirapine; non-nucleoside reverse transcriptase inhibitor; carcinogenicity; DNA adducts; palladium catalysis nevirapine; non-nucleoside reverse transcriptase inhibitor; carcinogenicity; DNA adducts; palladium catalysis
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Antunes, A.M.M.; Wolf, B.; Oliveira, M.C.; Beland, F.A.; Marques, M.M. 2'-Deoxythymidine Adducts from the Anti-HIV Drug Nevirapine. Molecules 2013, 18, 4955-4971.

AMA Style

Antunes AMM, Wolf B, Oliveira MC, Beland FA, Marques MM. 2'-Deoxythymidine Adducts from the Anti-HIV Drug Nevirapine. Molecules. 2013; 18(5):4955-4971.

Chicago/Turabian Style

Antunes, Alexandra M.M.; Wolf, Benjamin; Oliveira, M. C.; Beland, Frederick A.; Marques, M. M. 2013. "2'-Deoxythymidine Adducts from the Anti-HIV Drug Nevirapine." Molecules 18, no. 5: 4955-4971.

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