Unmasking efavirenz neurotoxicity: Time matters to the underlying mechanisms

N.M. Grilo, M. João Correia, J.P. Miranda, M. Cipriano, J. Serpa, M. Matilde Marques, E.C. Monteiro, A.M.M. Antunes, L.N. Diogo, S.A. Pereira

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20 Citations (Scopus)


Efavirenz is an anti-HIV drug that presents relevant short- and long-term central nervous system adverse reactions. Its main metabolite (8-hydroxy-efavirenz) was demonstrated to be a more potent neurotoxin than efavirenz itself. This work was aimed to understand how efavirenz biotransformation to 8-hydroxy-efavirenz is related to its short- and long-term neuro-adverse reactions. To access those mechanisms, the expression and activity of Cyp2b enzymes as well as the thiolomic signature (low molecular weight thiols plus S-thiolated proteins) were longitudinally evaluated in the hepatic and brain tissues of rats exposed to efavirenz during 10 and 36 days. Efavirenz and 8-hydroxy-efavirenz plasma concentrations were monitored at the same time points. Cyp2b induction had a delayed onset in liver (p <0.001), translating into increases in Cyp2b activity in liver and 8-hydroxy-efavirenz plasma concentration (p <0.001). Moreover, an increase in S-cysteinyl-glycinylated proteins (p <0.001) and in free low molecular weight thiols was also observed in liver. A distinct scenario was observed in hippocampus, which showed an underexpression of Cyp2b as well as a decrease in S-cysteinylated and S-glutathionylated proteins. Additionally, the observed changes in tissues were associated with a marked increase of S-glutathionylation in plasma. Our data suggest that the time course of efavirenz biotransformation results from different mechanisms for its short- and long-term neurotoxicity. The difference in the redox profile between liver and hippocampus might explain why, despite being mostly metabolized by the liver, this drug is neurotoxic. If translated to clinical practice, this evidence will have important implications in efavirenz short- and long-term neurotoxicity prevention and management. © 2017 Elsevier B.V.
Original languageEnglish
Pages (from-to)47-54
Number of pages8
JournalEuropean Journal Of Pharmaceutical Sciences
Publication statusPublished - 15 Jul 2017


  • 8-Hydroxy-efavirenz
  • CYP2B6
  • S-thiolated proteins
  • Thiolomic signature
  • Time-dependent CYP450 induction


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