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Human sulfotransferase 1A1-dependent mutagenicity of 12-hydroxy-nevirapine: the missing link?

Michel Kranendonk1, Mónica Alves, Pedro Antunes

  • 1Department of Genetics/CIGMH, NOVA Medical School/Faculdade Ciências Médicas, Universidade Nova de Lisboa , Rua da Junqueira 100, 1349-008 Lisbon, Portugal.

Chemical Research in Toxicology
|October 3, 2014
PubMed

Insights

Nevirapine, an anti-HIV drug, can cause severe toxicity. Its metabolite, 12-hydroxy-NVP, is mutagenic, explaining some of the drug's adverse effects.

Area of Science:

  • Pharmacology
  • Toxicology
  • Drug Metabolism

Background:

  • Nevirapine (NVP) is a critical antiretroviral medication for HIV treatment.
  • NVP is linked to severe skin and liver toxicities, and rodent studies show increased hepatoneoplasia.
  • Reactive metabolites, generated via cytochrome P450 and sulfonation, are implicated in NVP-induced toxicities.

Purpose of the Study:

  • To investigate the genotoxicity of Nevirapine (NVP) and its metabolites.
  • To determine if NVP metabolites contribute to the observed toxicities.
  • To elucidate the role of specific enzymes in NVP-induced mutagenicity.

Main Methods:

  • Standard in vitro genotoxicity assays were performed.
  • The mutagenicity of NVP metabolites, specifically 12-hydroxy-NVP, was assessed.
  • The involvement of human sulfotransferase 1A1 (SULT1A1) in metabolic activation was evaluated.

Main Results:

  • Standard genotoxicity tests did not reveal mutagenic or clastogenic potential for NVP itself.
  • 12-hydroxy-NVP, a major NVP metabolite, demonstrated mutagenicity.
  • This mutagenicity was dependent on the activity of human sulfotransferase 1A1 (SULT1A1).

Conclusions:

  • The mutagenicity of Nevirapine (NVP) is mediated by its metabolite 12-hydroxy-NVP.
  • Human sulfotransferase 1A1 (SULT1A1) plays a key role in activating 12-hydroxy-NVP, leading to genotoxicity.
  • This finding provides a mechanistic link between NVP metabolism and its potential to cause adverse effects, including hepatotoxicity.

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