| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 1998 Oxford University Press
other |
Induction of Oxidative Stress in Rat Brain by Acrylonitrile (ACN)
Department of Pharmacology and Toxicology, Division of Toxicology, Indiana University School of Medicine 635 Barnhill Drive, MS-1201, Indianapolis, Indiana 46202
Received January 16, 1998; accepted June 22, 1998
Chronic treatment with acrylonitrile (ACN) has been shown to produce a dose-related increase in glial cell tumors (astrocytomas) in rats. The mechanism(s) for ACN-induced carcinogenicity remains unclear. While ACN has been reported to induce DNA damage in a number of short-term systems, evidence for a genotoxic mechanism of tumor induction is the brain is not strong. Other toxic mechanisms appear to participate n the induction of tumor or induce the astrocytomas solely. In particular, nongenotoxic mechanisms of carcinogen induction have been implicated in this ACN-induced carcinogenic effect in the rat brain. One major pathway of ACN metabolism is through glutathione (GSH) conjugation. Extensive utilization and depletion of GSH, an important intracellular antioxidant, by ACN may lead to cellular oxidative stress. The present study examined the ability of ACN to induce oxidative stress in male Sprague-Dawley rats. Rats were administered ACN at concentrations of 0, 5, 10, 100, or 200 ppm in the drinking water and sampled after 14, 28, or 90 days of continuous treatment. Oxidative DNA damage indicated by the presence of 8-hydroxy-2'-deoxyguanosine (OH8dG) and lipid peroxidation indicated by the presence of malondialdehyde (MDA), a lipid peroxidation product, in rat brains and livers were examined. The levels of reactive oxygen species (ROS) were also determined in different rat tissues. Both the levels of nonenzymatic antioxidants (GSH, vitamin E) and the activities of enzymatic antioxidants (cata-lase, superoxide dismutase, glutathione peroxidase) in rat brains and livers were measured. Increased levels of OH8dG, MDA, and ROS were found in the brains of ACN-treated rats. Decreased levels of GSH and activities of catalase and SOD were also observed in the brains of ACN-treated rats compared to the control group. Interestingly, there were no changes of these indicators of oxidative stress in the livers of ACN-treated rats. Rat liver is not a target for ACN-induced carcinogenesis. These data indicate that ACN selectively induces oxidative stress in rat brain at doses that produce carcinogenesis in chronic treatment studies.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  L T Haber and J Patterson Report of an independent peer review of an acrylonitrile risk assessment Human and Experimental Toxicology, October 1, 2005; 24(10): 487 - 527. [Abstract] [PDF]
|
|
|
|
 |
|
 B. I. Ghanayem, A. Nyska, J. K. Haseman, and J. R. Bucher Acrylonitrile Is a Multisite Carcinogen in Male and Female B6C3F1 Mice Toxicol. Sci., July 1, 2002; 68(1): 59 - 68. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Zhang, L. M. Kamendulis, and J. E. Klaunig Mechanisms for the Induction of Oxidative Stress in Syrian Hamster Embryo Cells by Acrylonitrile Toxicol. Sci., June 1, 2002; 67(2): 247 - 255. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Zhang, L. M. Kamendulis, J. Jiang, Y. Xu, and J. E. Klaunig Acrylonitrile-induced morphological transformation in Syrian hamster embryo cells Carcinogenesis, April 1, 2000; 21(4): 727 - 733. [Abstract] [Full Text] [PDF]
|
|