Human Sulfotransferase 1A1-Dependent Mutagenicity of 12-Hydroxy-nevirapine: The Missing Link?

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Abstract

Nevirapine (NVP) is a frequently used anti-HIV drug. Despite its efficacy, NVP has been associated with serious skin and liver injuries in exposed patients and with increased incidences of hepatoneoplasias in rodents. Current evidence supports the involvement of reactive metabolites in the skin and liver toxicities of NVP, formed by cytochrome P450-mediated oxidations and/or subsequent phase II sulfonation. However, to date, standard in vitro genotoxicity tests have provided no evidence that NVP is either mutagenic or clastogenic. The human sulfotransferase 1A1-dependent mutagenidty of 12-hydroxy-NVP, one of the major metabolites of NVP, is demonstrated here.
Original languageEnglish
Pages (from-to)1967-1971
Number of pages5
JournalChemical Research In Toxicology
Volume27
Issue number11
DOIs
Publication statusPublished - 2014

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Nevirapine
Metabolites
Liver
Skin
Mutagenicity Tests
Anti-HIV Agents
Sulfonation
Cytochrome P-450 Enzyme System
Toxicity
human SULT1A1 protein
Rodentia
Oxidation
Incidence
Wounds and Injuries

Keywords

    Cite this

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    title = "Human Sulfotransferase 1A1-Dependent Mutagenicity of 12-Hydroxy-nevirapine: The Missing Link?",
    abstract = "Nevirapine (NVP) is a frequently used anti-HIV drug. Despite its efficacy, NVP has been associated with serious skin and liver injuries in exposed patients and with increased incidences of hepatoneoplasias in rodents. Current evidence supports the involvement of reactive metabolites in the skin and liver toxicities of NVP, formed by cytochrome P450-mediated oxidations and/or subsequent phase II sulfonation. However, to date, standard in vitro genotoxicity tests have provided no evidence that NVP is either mutagenic or clastogenic. The human sulfotransferase 1A1-dependent mutagenidty of 12-hydroxy-NVP, one of the major metabolites of NVP, is demonstrated here.",
    keywords = "REVERSE-TRANSCRIPTASE INHIBITOR, ACETYLTRANSFERASES, MECHANISM, POLYMORPHISMS, SKIN, NEVIRAPINE BIOACTIVATION, DNA-ADDUCTS, SALMONELLA-TYPHIMURIUM STRAINS, TOXICITY, ACTIVATION",
    author = "M Kranendonk and J. Rueff",
    year = "2014",
    doi = "10.1021/tx5003113",
    language = "English",
    volume = "27",
    pages = "1967--1971",
    journal = "Chemical Research In Toxicology",
    issn = "0893-228X",
    publisher = "ACS American Chemical Society",
    number = "11",

    }

    TY - JOUR

    T1 - Human Sulfotransferase 1A1-Dependent Mutagenicity of 12-Hydroxy-nevirapine: The Missing Link?

    AU - Kranendonk, M

    AU - Rueff, J.

    PY - 2014

    Y1 - 2014

    N2 - Nevirapine (NVP) is a frequently used anti-HIV drug. Despite its efficacy, NVP has been associated with serious skin and liver injuries in exposed patients and with increased incidences of hepatoneoplasias in rodents. Current evidence supports the involvement of reactive metabolites in the skin and liver toxicities of NVP, formed by cytochrome P450-mediated oxidations and/or subsequent phase II sulfonation. However, to date, standard in vitro genotoxicity tests have provided no evidence that NVP is either mutagenic or clastogenic. The human sulfotransferase 1A1-dependent mutagenidty of 12-hydroxy-NVP, one of the major metabolites of NVP, is demonstrated here.

    AB - Nevirapine (NVP) is a frequently used anti-HIV drug. Despite its efficacy, NVP has been associated with serious skin and liver injuries in exposed patients and with increased incidences of hepatoneoplasias in rodents. Current evidence supports the involvement of reactive metabolites in the skin and liver toxicities of NVP, formed by cytochrome P450-mediated oxidations and/or subsequent phase II sulfonation. However, to date, standard in vitro genotoxicity tests have provided no evidence that NVP is either mutagenic or clastogenic. The human sulfotransferase 1A1-dependent mutagenidty of 12-hydroxy-NVP, one of the major metabolites of NVP, is demonstrated here.

    KW - REVERSE-TRANSCRIPTASE INHIBITOR

    KW - ACETYLTRANSFERASES

    KW - MECHANISM

    KW - POLYMORPHISMS

    KW - SKIN

    KW - NEVIRAPINE BIOACTIVATION

    KW - DNA-ADDUCTS

    KW - SALMONELLA-TYPHIMURIUM STRAINS

    KW - TOXICITY

    KW - ACTIVATION

    U2 - 10.1021/tx5003113

    DO - 10.1021/tx5003113

    M3 - Article

    VL - 27

    SP - 1967

    EP - 1971

    JO - Chemical Research In Toxicology

    JF - Chemical Research In Toxicology

    SN - 0893-228X

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    ER -