PT  - JOURNAL ARTICLE
AU  - Nils Helge Schebb
AU  - Jaya B. Muvvala
AU  - Dexter Morin
AU  - Alan R. Buckpitt
AU  - Bruce D. Hammock
AU  - Robert H. Rice
TI  - Metabolic Activation of the Antibacterial Agent Triclocarban by Cytochrome P450 1A1 Yielding Glutathione Adducts
AID  - 10.1124/dmd.114.058206
DP  - 2014 Jul 01
TA  - Drug Metabolism and Disposition
PG  - 1098--1102
VI  - 42
IP  - 7
4099  - http://dmd.aspetjournals.org/content/42/7/1098.short
4100  - http://dmd.aspetjournals.org/content/42/7/1098.full
SO  - Drug Metab Dispos2014 Jul 01; 42
AB  - 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.