Cytotoxic effects of polychlorinated biphenyl hydroquinone metabolites in rat hepatocytes.
Polychlorinated biphenyls (PCBs) are persistent organic pollutants that exhibit various toxic effects in animals and exposed human populations. The molecular mechanisms of PCB toxicity have been attributed to the toxicological properties of its metabolites, such as hydroquinones, formed by cytochrome-P-450 oxidation. The effects of PCB hydroquinone metabolites towards freshly isolated rat hepatocytes were investigated. Hydroquinones can be oxidized to semiquinones and/or quinone metabolites. These metabolites can conjugate glutathione or can oxidize glutathione as a result of redox cycling. This depletes hepatocyte glutathione, which can inhibit cellular defence mechanisms, causing cell death and an increased susceptibility to oxidative stress. However in the following, glutathione-depleted hepatocytes became more resistant to the hydroquinone metabolites of PCBs. This suggested that their glutathione conjugates were toxic and that there was a third type of quinone toxicity mechanism which involved a hydrogen peroxide-accelerated autoxidation of the hydroquinones to form toxic electrophilic quinone and semiquinone-glutathione conjugates.
Chan
Katie
K
Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, 144 College St., Toronto, ON, Canada M5S 3M2.
Lehmler
Hans-Joachim
HJ
Sivagnanam
Milani
M
Feng
Cynthia Yan
CY
Robertson
Larry
L
O'Brien
Peter J
PJ
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism / Q000494:pharmacology; D022781:Hepatocytes / Q000378:metabolism*; D006873:Hydroquinones / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D010084:Oxidation-Reduction; D011078:Polychlorinated Biphenyls / Q000378:metabolism*; D011809:Quinones / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D006873:Hydroquinones; D011809:Quinones; D011078:Polychlorinated Biphenyls; D005978:Glutathione; C031927:hydroquinone