Nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor (NNRTI), is one of the most widely used anti-HIV drugs in developing countries. Although NVP is not mutagenic or clastogenic it is reported to induce neoplasms in rodents [1]. While a direct correlation between NVP administration and human cancer has yet to be demonstrated, epidemiological data indicate a possible association between chronic use of NNRTIs and the occurrence of non-AIDS-defining cancers in HIV-positive patients [2], suggesting that NNRTIs may be carcinogenic in humans.Evidence for protein adduct formation by NVP in rodents and humans was recently presented by our research group [3]. By contrast, we found no indication of DNA adduct formation by NVP in rodent models in vivo. These data, combined with a preliminary report of NVP-induced epigenetic alterations in rat liver [4], led us to hypothesize that NVP can covalently modify histones, triggering epigenetic phenomena that may underlie the onset of NVP-induced cancers.Using mass spectrometry, we now present evidence for in vitro modification of multiple lysines in the histone octamer by 12-mesyloxy-NVP, a validated synthetic surrogate [5] of the reactive NVP metabolite, 12-sulfoxy-NVP. In vivo studies in rats exposed to NVP are currently underway to examine possible correlations between the incidence of NVP-histone modifications (and their locations) and epigenetic changes potentially leading to cancer.[1] VIRAMUNE� (Nevirapine). In Physicians' Desk Reference, 63rd ed, PDR Inc, Montvale, NJ, 2009, 873[2] Powles et al, J Clin Oncol, 2009, 27, 884[3] Caixas et al, Toxicology, 2012, 301, 33[4] Pereira et al,Environ Mol Mutagen, 2010, 51, 699[5] Antunes et al.Chem Res Toxicol. 2010, 23, 888We thank FCT, Portugal (PTDC/QUI-QUI/113910/2009, PEst-OE/QUI/UI0100/2013, and RECI/QEQ-MED/0330/2012) and the Portuguese MS network. Thanks are also due to the PRIME-XS consortium and the 7th FP-EU for access to proteomics facilities (grant PRIME-XS-0000160).

Covalent histone modification by nevirapine: Potential association with non-AIDS defining cancers

248th National Meeting (2014)

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