Oxidative stress induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is one of the most potent toxins and tumor promoters known to man. It is prototypical of many halogenated polycyclic hydrocarbons that occur as environmental contaminants. Pathologic lesions produced by these compounds are mediated by an intracellular receptor protein called the TCDD (Ah) receptor which functions as a trans-acting effector of gene expression. However, the ultimate posttranslational pathways and mechanisms involved in the expression of the toxic manifestations of TCDD have received little attention and remain unclear, yet constitute an important segment in our understanding of the overall mechanism of action of TCDD. Recent studies have demonstrated that an oxidative stress occurs in various tissues of TCDD-treated animals. Evidence indicating production of an oxidative stress by TCDD in rodents is reviewed and includes:enhanced in vitro and in vivo hepatic and extrahepatic lipid peroxidation; increased hepatic and macrophage DNA damage; increased urinary excretion of malondialdehyde; decreased hepatic membrane fluidity; increased production of superoxide anion by peritoneal macrophage; and decreased glutathione, nonprotein sulfhydryl, and NADPH contents in liver. The potential role of reactive oxygen species in tumor promotion by TCDD is discussed. Possible sources and mechanisms of production of reactive oxygen species in response to TCDD are considered in light of current information. Evidence demonstrating the involvement of iron in TCDD-induced formation of reactive oxygen species and DNA damage is reviewed. Oxidative damage may contribute to many of the toxic responses produced by TCDD and its bioisosteres, and may be common to most of the tissue-damaging effects.
Stohs
S J
SJ
School of Pharmacy and Allied Health, Creighton University Health Sciences Center, Omaha, NE 68178.
D000818:Animals; D002273:Carcinogens; D005609:Free Radicals; D015227:Lipid Peroxidation / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism*; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*
D002273:Carcinogens; D005609:Free Radicals; D000072317:Polychlorinated Dibenzodioxins; D010100:Oxygen