S-thiolated protein profile to assess the redox-modulation effects of antiretroviral drugs

Abstract

Efavirenz (EFV) is an anti-HIV drug that has been associated to neurotoxicity. The 8-hydroxy-efavirenz metabolite has been described as the responsible for its long-term neurotoxic effects. Upon bioactivation this metabolite is able to generate electrophilic species, forming protein adducts and eliciting oxidative stress. S-thiolation of proteins (e.g. S-glutathionylation) has been suggested as a mechanism of protein regulation by the redox status. The present study is aimed to investigate if S-thiolated proteins plasma profile (RSSP) is associated with EFV-neurotoxicity. The RSSP was assessed in an animal model of EFV-induced neurotoxicity. The animal RSSP was compared to the one obtained in a cohort of HIV-infected patients on EFV. The dependence on 8-hydroxy-efavirenz generation and the influence of infection in RSSP profile were also assessed in the clinical study. This profile was also compared to the one obtained in patients on nevirapine (NVP), a non-neurotoxic antiretroviral of the same class of EFV. The same RSSP was found in animal model and patients on EFV. This profile is characterized by increased S-glutathionylation and decreased S-cysteinylation of proteins. This is mainly observed in patients that form higher 8-hydroxy-efavirenz, which is in accordance with higher risk of neurotoxicity. RSSP of patients on NVP was the opposite of the one observed for EFV. This might explain why EFV is mostly metabolized by liver, but is barely hepatotoxic. No influence of HIV-infection in RSSP was found. Summing up, we conclude that RSSP profile might be associated with EFV-induced neurotoxicity, suggesting that it is a suitable tool for therapeutic drug monitoring aimed at managing toxic events. Moreover, as EFV and NVP presented a different RSSP signature, this tool might be used for assessing antiretroviral redox-modulation effects and quantification of drug-induced oxidative stress. This knowledge might have important implications for toxicity risk assessment, antiretroviral prescription and drug development.