title: Urinary naphthalene mercapturates as biomarkers of exposure and stereoselectivity of naphthalene epoxidation.
abstract: Previous work has shown that the rate and stereochemistry of naphthalene epoxidation correlates with differences in susceptibility to cytotoxicity. The development of methods for measuring epoxide formation in vivo could provide a marker for assessing events critical to naphthalene cytotoxicity that are applicable to humans. Here, urinary diastereomeric mercapturates have been measured in mice (susceptible) and rats (nonsusceptible) after intraperitoneal administration (1.56-200 mg/kg) or inhalation exposures (0.8-110 ppm, 4 h) to naphthalene. No significant differences were observed in the percentage of the dose eliminated as mercapturate in urine between mice (25-34%) and rats (24-35%) or at varying doses after i.p. administration. The amounts of urinary mercapturate after 4-h exposures were considerably greater in mice than rats. In mice, the ratio of diastereomeric mercapturates derived from the 1R,2S- to 1S,2R-epoxide was 1:1 at low doses (1-3 mg/kg), increased to 3:1 at intermediate doses (50 mg/kg), and decreased to 2:1 at high doses (100 and 200 mg/kg). In rats, these ratios remained less than 1:1 at all doses. After inhalation, ratios were 5 to 6:1 at low concentrations (less than 15 ppm) and decreased to 3:1 at higher concentrations (15-100 ppm) in mice, whereas in rats, the ratios were 1:1 or less for all concentrations. These studies show that mercapturates provide good assessments of internal dose, that there are not significant differences between mice and rats in the percentage eliminated as mercapturate but that the ratios of mercapturates derived from the 1R,2S- versus 1S,2R-epoxide differ markedly and are consistent with previous in vitro metabolism studies.
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616, USA.
authors.forename: Gwyn
authors.initials: G
authors.lastname: Pakenham
authors.forename: Jozsef
authors.initials: J
authors.lastname: Lango
authors.forename: Michael
authors.initials: M
authors.lastname: Buonarati
authors.forename: Dexter
authors.initials: D
authors.lastname: Morin
authors.forename: Alan
authors.initials: A
authors.lastname: Buckpitt
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000652:urine*; D000280:Administration, Inhalation; D000818:Animals; D015415:Biomarkers / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure; D004785:Environmental Pollutants / Q000378:metabolism / Q000633:toxicity / Q000652:urine*; D004852:Epoxy Compounds / Q000378:metabolism* / Q000633:toxicity; D007263:Infusions, Parenteral; D008297:Male; D051379:Mice; D009281:Naphthalenes / Q000378:metabolism / Q000633:toxicity / Q000652:urine*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism; D013379:Substrate Specificity
chemical_list: D015415:Biomarkers; D004785:Environmental Pollutants; D004852:Epoxy Compounds; D009281:Naphthalenes; C031721:naphthalene; D000111:Acetylcysteine