Metabolic activation of the antibacterial agent triclocarban by cytochrome P450 1A1 yielding glutathione adducts

Nils Helge Schebb, Jaya B. Muvvala, Dexter Morin, Alan R Buckpitt, Bruce D. Hammock, Robert H. Rice

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 cytochrome P450 reductase, glutathione-S-transferases (GSH), 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 hours. 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.

Original languageEnglish (US)
Pages (from-to)1098-1102
Number of pages5
JournalDrug Metabolism and Disposition
Volume42
Issue number7
DOIs
StatePublished - 2014

Fingerprint

Cytochrome P-450 CYP1A1
Keratinocytes
Cytochrome P-450 Enzyme System
Glutathione
Anti-Bacterial Agents
Soaps
NADPH-Ferrihemoprotein Reductase
Imines
Anti-Infective Agents
Glutathione Transferase
NADP
Epidermis
Mass Spectrometry
Proteins
Metabolic Activation
triclocarban
Polychlorinated Dibenzodioxins

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Medicine(all)

Cite this

Metabolic activation of the antibacterial agent triclocarban by cytochrome P450 1A1 yielding glutathione adducts. / Schebb, Nils Helge; Muvvala, Jaya B.; Morin, Dexter; Buckpitt, Alan R; Hammock, Bruce D.; Rice, Robert H.

In: Drug Metabolism and Disposition, Vol. 42, No. 7, 2014, p. 1098-1102.

Research output: Contribution to journalArticle

Schebb, Nils Helge ; Muvvala, Jaya B. ; Morin, Dexter ; Buckpitt, Alan R ; Hammock, Bruce D. ; Rice, Robert H. / Metabolic activation of the antibacterial agent triclocarban by cytochrome P450 1A1 yielding glutathione adducts. In: Drug Metabolism and Disposition. 2014 ; Vol. 42, No. 7. pp. 1098-1102.
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