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

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",

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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

IS - 11

ER -