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 Iow 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 247-253 |
| Number of pages | 7 |
| Journal | Drug Metabolism and Disposition |
| Volume | 30 |
| Issue number | 3 |
| DOIs | |
| State | Published - 2002 |
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ASJC Scopus subject areas
- Pharmacology
- Toxicology
Cite this
Urinary naphthalene mercapturates as biomarkers of exposure and stereoselectivlty of naphthalene epoxidation. / Pakenham, Gwyn; Lango, Jozsef; Buonarati, Michael; Morin, Dexter; Buckpitt, Alan R.
In: Drug Metabolism and Disposition, Vol. 30, No. 3, 2002, p. 247-253.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Urinary naphthalene mercapturates as biomarkers of exposure and stereoselectivlty of naphthalene epoxidation
AU - Pakenham, Gwyn
AU - Lango, Jozsef
AU - Buonarati, Michael
AU - Morin, Dexter
AU - Buckpitt, Alan R
PY - 2002
Y1 - 2002
N2 - 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 Iow 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.
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 Iow 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.
UR - http://www.scopus.com/inward/record.url?scp=0036183434&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036183434&partnerID=8YFLogxK
U2 - 10.1124/dmd.30.3.247
DO - 10.1124/dmd.30.3.247
M3 - Article
C2 - 11854141
AN - SCOPUS:0036183434
VL - 30
SP - 247
EP - 253
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
SN - 0090-9556
IS - 3
ER -