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Toxicological Sciences 67, 247-255 (2002)
Copyright © 2002 by the Society of Toxicology

MOLECULAR AND GENETIC TOXICOLOGY

Mechanisms for the Induction of Oxidative Stress in Syrian Hamster Embryo Cells by Acrylonitrile

Haizhou Zhang, Lisa M. Kamendulis and James E. Klaunig,1

Division of Toxicology, Department of Pharmacology and Toxicology, Indiana University School of Medicine, MS 1021, 635 Barnhill Drive, Indianapolis, Indiana 46202

Chronic administration of acrylonitrile to rats resulted in an increase in the incidence of glial neoplasms of the brain. Recent studies have shown that acrylonitrile induces oxidative stress in rat brain and cultured rat glial cells. Acrylonitrile also induces morphological transformation concomitant with an increase in the formation of oxidized DNA in Syrian Hamster Embryo (SHE) cells in a dose-dependent manner. The mechanism for the induction of oxidative stress in SHE cells remains unresolved. The present study examined the effects of acrylonitrile on enzymatic and nonenzymatic antioxidants in SHE cells. SHE cells were treated with subcytolethal doses of acrylonitrile (0, 25, 50, and 75 µg/ml) for 4, 24, and 48 h. Acrylonitrile (50 µg/ml and 75µg/ml) increased the amount of reactive oxygen species in SHE cells at all time points. Glutathione (GSH) was depleted and catalase and superoxide dismutase activities were significantly decreased in SHE cells after 4 h of treatment. The inhibition of these antioxidants was temporal, returning to control values or higher after 24 and 48 h. Xanthine oxidase activity was increased following 24 and 48 h treatment with acrylonitrile. 1-aminobenzotriazole, a suicidal P450 enzyme inhibitor, attenuated the effects of acrylonitrile on catalase and xanthine oxidase in SHE cells, suggesting that P450 metabolism is required for acrylonitrile to produce its effects on these enzymes. Additional studies showed that in the absence of metabolic sources acrylonitrile had no effect on either catalase or superoxide dismutase activity. These results suggest that the induction of oxidative stress by acrylonitrile involves a temporal decrease in antioxidants and increase in xanthine oxidase activity that is mediated by oxidative metabolism of acrylonitrile.

Key Words: acrylonitrile; catalase; glutathione; oxidative stress; SHE cells; superoxide dismutase; xanthine oxidase.


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