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ToxSci Advance Access originally published online on February 19, 2004
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Toxicological Sciences 79, 18-27 (2004)
Toxicological Sciences vol. 79 no. 1 © Society of Toxicology; all rights reserved.

Kinetic Modeling of ß-Chloroprene Metabolism: I. In vitro Rates in Liver and Lung Tissue Fractions from Mice, Rats, Hamsters, and Humans

Matthew W. Himmelstein1, Steven C. Carpenter and Paul M. Hinderliter

E.I. du Pont de Nemours and Company, Haskell Laboratory for Health and Environmental Sciences, PO Box 50, 1090 Elkton Road, Newark, Delaware 19711

Received October 18, 2003; accepted January 26, 2004

Beta-chloroprene (2-chloro-1,3-butadiene, CD) is carcinogenic by inhalation exposure to B6C3F1 mice and Fischer F344 rats but not to Wistar rats or Syrian hamsters. The initial step in metabolism is oxidation, forming a stable epoxide (1-chloroethenyl)oxirane (1-CEO), a genotoxicant that might be involved in rodent tumorigenicity. This study investigated the species-dependent in vitro kinetics of CD oxidation and subsequent 1-CEO metabolism by microsomal epoxide hydrolase and cytosolic glutathione S-transferases in liver and lung, tissues that are prone to tumor induction. Estimates for Vmax and Km for cytochrome P450-dependent oxidation of CD in liver microsomes ranged from 0.068 to 0.29 µ;mol/h/mg protein and 0.53 to 1.33 µ;M, respectively. Oxidation (Vmax/Km) of CD in liver was slightly faster in the mouse and hamster than in rats or humans. In lung microsomes, Vmax/Km was much greater for mice compared with the other species. The Vmax and Km estimates for microsomal epoxide hydrolase activity toward 1-CEO ranged from 0.11 to 3.66 µ;mol/h/mg protein and 20.9 to 187.6 µ;M, respectively, across tissues and species. Hydrolysis (Vmax/Km) of 1-CEO in liver and lung microsomes was faster for the human and hamster than for rat or mouse. The Vmax/Km in liver was 3 to 11 times greater than in lung. 1-CEO formation from CD was measured in liver microsomes and was estimated to be 2–5% of the total CD oxidation. Glutathione S-transferase-mediated metabolism of 1-CEO in cytosolic tissue fractions was described as a pseudo-second order reaction; rates were 0.0016–0.0068/h/mg cytosolic protein in liver and 0.00056–0.0022 h/mg in lung. The observed differences in metabolism are relevant to understanding species differences in sensitivity to CD-induced liver and lung tumorigenicity.

Key Words: 2-chloro-1,3-butadiene; microsomes; cytosol; liver; lung; mouse; rat; hamster; human; in vitro kinetics.


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M. W. Himmelstein, S. C. Carpenter, M. V. Evans, P. M. Hinderliter, and E. M. Kenyon
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[Abstract] [Full Text] [PDF]


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