RT Journal Article
SR Electronic
T1 Urinary Naphthalene Mercapturates as Biomarkers of Exposure and Stereoselectivity of Naphthalene Epoxidation
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 247
OP 253
DO 10.1124/dmd.30.3.247
VO 30
IS 3
A1 Gwyn Pakenham
A1 Jozsef Lango
A1 Michael Buonarati
A1 Dexter Morin
A1 Alan Buckpitt
YR 2002
UL http://dmd.aspetjournals.org/content/30/3/247.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics