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Research ArticleShort Communication

Metabolic Activation of the Antibacterial Agent, Triclocarban, by Cytochrome P450 1A1 Yielding Glutathione Adducts

Nils H Schebb, Jaya B Muvvala, Dexter Morin, Alan R Buckpitt, Bruce D Hammock and Robert H Rice
Drug Metabolism and Disposition April 14, 2014, dmd.114.058206; DOI: https://doi.org/10.1124/dmd.114.058206
Nils H Schebb
1 University of Veterinary Medicine Hannover;
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  • For correspondence: schebb@wwu.de
Jaya B Muvvala
2 Department of Molecular Biosciences (JB, DM,, School of Veterinary Medicine, UC Davis, CA, USA;
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Dexter Morin
2 Department of Molecular Biosciences (JB, DM,, School of Veterinary Medicine, UC Davis, CA, USA;
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Alan R Buckpitt
2 Department of Molecular Biosciences (JB, DM,, School of Veterinary Medicine, UC Davis, CA, USA;
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Bruce D Hammock
3 Department of Entomology and Comprehensive Cancer Center, CA, USA;
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Robert H Rice
4 Environmental Toxicology, College of Agricultural and Environmental Sciences , UC Davis, CA, USA
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Abstract

Triclocarban (3,4,4'-trichlorocarbanilide; TCC) is an antibacterial agent used in personal care products such as bar soaps. Small amounts of chemical are absorbed through the epidermis. Recent studies show that residues of reactive TCC metabolites are bound covalently to proteins in incubations with keratinocytes, raising concerns about the potential toxicity of this antimicrobial agent. To obtain additional information on metabolic activation of TCC, this study characterized the reactive metabolites trapped as glutathione conjugates. Incubations were carried out with 14C-labeled TCC, recombinant CYP1A1 or CYP1B1 coexpressed with P450 reductase, GSH, glutathione S-transferases and an NADPH generating system. Incubations containing CYP1A1, but not 1B1, led to formation of a single TCC-GSH adduct with a conversion rate of 1% of parent compound in 2 hr. Using high resolution mass spectrometry and diagnostic fragmentation, the adduct was tentatively identified as 3,4-dichloro-3'-glutathionyl-4'-hydroxycarbanilide. These findings support the hypothesis that TCC is activated by oxidative dehalogenation and oxidation to a quinone imine. Incubations of TCDD-induced keratinocytes with 14C-TCC yielded a minor radioactive peak coeluting with TCC-GSH. Thus, we conclude that covalent protein modification by TCC in TCDD-induced human keratinocyte incubations is mainly caused by activation of TCC by CYP1A1 via a dehalogenated TCC derivative as reactive species.

  • bioactivation
  • CYP1A
  • glutathione homeostasis
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 51 (10)
Drug Metabolism and Disposition
Vol. 51, Issue 10
1 Oct 2023
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Research ArticleShort Communication

Metabolic Activation of the Antibacterial Agent, Triclocarban, by Cytochrome P450 1A1 Yielding Glutathione Adducts

Nils H Schebb, Jaya B Muvvala, Dexter Morin, Alan R Buckpitt, Bruce D Hammock and Robert H Rice
Drug Metabolism and Disposition April 14, 2014, dmd.114.058206; DOI: https://doi.org/10.1124/dmd.114.058206

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Research ArticleShort Communication

Metabolic Activation of the Antibacterial Agent, Triclocarban, by Cytochrome P450 1A1 Yielding Glutathione Adducts

Nils H Schebb, Jaya B Muvvala, Dexter Morin, Alan R Buckpitt, Bruce D Hammock and Robert H Rice
Drug Metabolism and Disposition April 14, 2014, dmd.114.058206; DOI: https://doi.org/10.1124/dmd.114.058206
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