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ToxSci Advance Access published online on February 19, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh092
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received October 18, 2003; accepted January 26, 2004
© 2004 Society of Toxicology

Biotransformation and Toxicokinetics

Kinetic Modeling of {beta}-Chloroprene Metabolism: I. In Vitro Rates in Liver and Lung Tissue Fractions from Mice, Rats, Hamsters, and Humans

Matthew W. Himmelstein 1*, Steven C. Carpenter 1, and Paul M. Hinderliter 1

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

* To whom correspondence should be addressed. E-mail: matthew.w.himmelstein{at}usa.dupont.com.


  Abstract

Beta-chloroprene (2-chloro-1,3-butadiene, CD) is carcinogenic by inhalation exposure to B6C3F1 mice and Fischer F344 rats but not Wistar rats or Syrian hamsters. The initial step in metabolism is oxidation, forming a stable epoxide, (1-chloroethenyl)oxirane (1-CEO), a genotoxicant which may 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 0.068-0.29 µmol/h/mg protein and 0.53-1.33 µM, respectively. Oxidation (Vmax/Km) of CD in liver was slightly faster in the mouse and hamster than 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 µmol/h/mg protein and 20.9 to 187.6 µM, 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-1mg-1 cytosolic protein in liver and 0.00056-0.0022 h-1mg-1 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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