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ToxSci Advance Access published online on May 12, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh170
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received March 8, 2004
Accepted May 6, 2004

Biotransformation and Toxicokinetics

Effect of Ethylene Exposure on Ethylene Oxide in Blood and on Hepatic Cytochrome P450 in Fischer Rats

Timothy R. Fennell 1*, Rodney W. Snyder 1, Carl Parkinson 1, John Murphy 1, R. Arden James 1

1 CIIT Centers for Health Research, P.O. Box 12137, Research Triangle Park, NC 27709

* To whom correspondence should be addressed. E-mail: fennell{at}rti.org.


  Abstract

Ethylene (74-85-1) is an important petrochemical, and is produced endogenously. It is metabolized to ethylene oxide (EO) via cytochrome P-450. This study investigated the inhibition of cytochrome P-450 activity during exposure to ethylene, and verified that this inhibition was reflected in the concentration of EO in the blood. Male F-344 rats were exposed to 1000, 600, and 300 ppm ethylene by nose only inhalation for up to 6 h. Blood samples were obtained during exposure. On exposure to 600 ppm ethylene, blood EO concentration increased during the first hour of exposure, and then decreased to approximately half of the peak blood concentration. A less pronounced decrease was observed at 300 ppm, and at 1000 ppm, little change was observed between 10 min and 6 h of exposure. For the analysis of cytochrome P450, and for isozyme-specific substrate activities, groups of 4 male F-344 rats were removed for collection of liver at various times after exposure to 300, 600 or 1000 ppm ethylene. At all concentrations, liver microsomal cytochrome P450 decreased during exposure. Of the various monooxygenase activities measured, 4-nitrophenol hydroxylase was the one most consistently altered, with maximal inhibition (approximately 50%) at 2 hours of exposure to 1000 ppm ethylene, 4 hours at 600 ppm and 6 hours at 300 ppm. Activity recovered to control levels by 6 hours after exposure. Cytochrome P4502E1 appears to be the major isoform of cytochrome P450 inhibited by exposure to ethylene, and this may explain in part the observed alteration in EO blood kinetics.


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