Cutaneous metabolic activation of carvoxime, a self-activating, skin-sensitizing prohapten

Chemical Research in Toxicology
H OttAnn-Therese Karlberg

Abstract

Bioactivation of low molecular weight compounds in the skin can cause contact sensitization. We have previously shown that the alpha, beta-R-unsaturated oxime R-carvoxime [1, (R)-2-methyl-5-isopropenylcyclohex-2-enone oxime] is bioactivated to two diastereomeric highly reactive and strongly sensitizing alpha, beta-epoxy oxime metabolites. To investigate if this metabolic activation is catalyzed by the major cytochrome P450 (P450) enzymes found in human skin, incubations of 1 with a skinlike P450 cocktail in the presence of glutathione were carried out. We identified three glutathione conjugates in the incubation mixture arising from two diasteomeric alpha, beta-epoxy oxime metabolites of 1, thus showing that the metabolic activation of 1 is P450-mediated. A P450 identification study using the individual P450 enzymes present in the skinlike P450 cocktail showed the involvement of P450 1A1 and 1B1 and also to some extent 2B6. P450 1B1 metabolism of 1 was found to be stereoselective as glutathione conjugates from only one of the alpha, beta-epoxyoxime metabolites were identified (metabolite 2). Additionally, 1 was found to be an inducer of P450 1B1 (but not 1A1) in human monocyte-derived dendritic cells (moDCs) and to some extent ...Continue Reading

References

May 4, 1999·International Archives of Allergy and Immunology·S SiebenH F Merk
Jun 21, 2001·Chemical Research in Toxicology·F P Guengerich
Jan 29, 2002·International Immunopharmacology·Ian KimberRebecca J Dearman
Aug 17, 2002·Toxicology and Applied Pharmacology·Ben A HuletteG Frank Gerberick
Aug 12, 2004·The Journal of Investigative Dermatology·Nihal Ahmad, Hasan Mukhtar
Jun 25, 2005·Current Drug Metabolism·Amit S KalgutkarShawn P Harriman
Jun 28, 2005·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Anna-Malin NilssonAnn-Therese Karlberg
Jun 29, 2005·The Journal of Investigative Dermatology·Jens M BaronFrank K Jugert
Jul 8, 2005·Toxicology and Applied Pharmacology·Rob J VandebrielHenk van Loveren
Aug 16, 2005·Toxicology in Vitro : an International Journal Published in Association with BIBRA·M J ToebakS Gibbs
Nov 25, 2006·The Journal of Investigative Dermatology·Moa Andresen BergströmJens M Baron
Mar 9, 2007·Contact Dermatitis·Jacob Pontoppidan ThyssenTorkil Menné
May 12, 2007·Toxicology and Applied Pharmacology·Cindy A RyanG Frank Gerberick
Dec 7, 2007·Chemical Research in Toxicology·Ann-Therese KarlbergJ Lars G Nilsson
Mar 29, 2008·Journal of Medicinal Chemistry·Moa Andresen BergströmAnn-Therese Karlberg

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Citations

Jul 12, 2011·Toxicological Sciences : an Official Journal of the Society of Toxicology·Jenny HennenBrunhilde Blömeke
Mar 30, 2013·Toxicological Sciences : an Official Journal of the Society of Toxicology·Nicola J HewittStefan Pfuhler
Jul 23, 2013·Toxicological Sciences : an Official Journal of the Society of Toxicology·Andreas Natsch, Tina Haupt
May 3, 2011·Archives of Toxicology·Sarah AdlerJosé-Manuel Zaldivar
Apr 5, 2012·Journal of Immunotoxicology·Christine JäckhRobert Landsiedel
Jul 27, 2011·Cutaneous and Ocular Toxicology·Hongbo ZhaiHoward Maibach
Mar 8, 2011·Toxicology and Applied Pharmacology·Itai ChipindaPaul D Siegel
Mar 21, 2013·Contact Dermatitis·Lina HagvallJohanna B Christensson
Oct 18, 2011·Toxicology in Vitro : an International Journal Published in Association with BIBRA·B ReesS Gibbs
Sep 16, 2009·Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG·Jens Malte Baron, Claudia Skazik
Jun 19, 2009·Current Opinion in Allergy and Clinical Immunology·Hans F Merk
Jul 2, 2009·Current Opinion in Allergy and Clinical Immunology

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