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.
Footnotes
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↵1 Present address: Aventis Pharmaceuticals, 399 Interpace Pkwy., P.O. Box 663, Parsipanny, NJ 07054.
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↵2 Present address: ALTA Analytical Laboratories, 5070 Robert J. Matthews Pkwy., El Dorado Hills, CA 95762.
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This research was supported by National Institute of Environmental Health Sciences Grant P01 04699. University of California, Davis, is a National Institute of Environmental Health Sciences Center in Environmental Sciences, and support for core facilities used in this work is gratefully acknowledged (ES 05707).
- Abbreviations used are::
- HPLC
- high-performance liquid chromatography
- ESI
- electrospray ionization
- Received July 25, 2001.
- Accepted December 3, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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