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ToxSci Advance Access originally published online on May 12, 2004
Toxicological Sciences 2004 81(1):7-13; doi:10.1093/toxsci/kfh170
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Toxicological Sciences vol. 81 no. 1 © Society of Toxicology 2004; all rights reserved.

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

Timothy R. Fennell1,2, Rodney W. Snyder1, Carl Parkinson, John Murphy and R. Arden James

CIIT Centers for Health Research, Research Triangle Park, North Carolina 27709

Received March 8, 2004; accepted May 6, 2004

Ethylene (74-85-1) is an important petrochemical and is produced endogenously. It is metabolized to ethylene oxide (EO) by cytochrome P450. We studied the inhibition of cytochrome P450 activity during exposure to ethylene, and verified that this inhibition was reflected in the concentration of EO in the blood. Male F344 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 isozyme-specific substrate activities, groups of four male F344 rats were removed for the 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 h of exposure to 1000 ppm ethylene, 4 h at 600 ppm, and 6 h at 300 ppm. Activity recovered to control levels by 6 h after exposure. Cytochrome P450 2E1 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.

Key Words: ethylene; ethylene oxide; cytochrome P450; metabolism; CYP 2E1.


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