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2'-Deoxythymidine Adducts from the Anti-HIV Drug Nevirapine
Centro de Química Estrutural, Instituto Superior Técnico, Universidade Técnica de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA
* Authors to whom correspondence should be addressed.
Received: 12 March 2013; in revised form: 18 April 2013 / Accepted: 19 April 2013 / Published: 26 April 2013
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
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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.
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.
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.