Redox cycling of 2-(x'-mono, -di, -trichlorophenyl)- 1, 4-benzoquinones, oxidation products of polychlorinated biphenyls.
Polychlorinated biphenyl (PCB) preparations are complete liver carcinogens in rodents and efficacious promoters in two-stage hepatocarcinogenesis. Cytochrome P450 isozymes catalyze the oxidation of PCBs to mono- and dihydroxy metabolites. The potential for further enzymatic or nonenzymatic oxidation of ortho- and para-dihydroxy PCB metabolites to (semi)quinones raises the possibility that redox cycling involving reactive oxygen species may be involved in PCB toxicity. Seven synthetic 2-(x'-chlorophenyl)-1, 4-benzoquinones (containing one to three chlorines) were investigated for their participation in oxidation-reduction reactions by following the oxidation of NADPH. These observations were made: (i) NADPH alone directly reduced all quinones but only 2-(2'-chlorophenyl)- and 2-(4'-chlorophenyl)-1,4-benzoquinone supported NADPH consumption beyond that required to quantitatively reduce the quinone. (ii) For all quinones, superoxide dismutase increased NADPH oxidation in excess of the amount of quinone, demonstrating the participation of the superoxide radical. (iii) The presence of microsomal enzymes from rat liver increased the rate of NADPH consumption, but only 2-(2'-chlorophenyl)- and 2-(4'-chlorophenyl)-1,4-benzoquinone autoxidized. (iv) The combination of superoxide dismutase with microsomal enzymes accelerated autoxidation from 1.6- to 6.8-fold higher than that found in the absence of microsomal protein. These data support the concept that in the absence of microsomal protein, there occurs a two-electron reduction of the quinone by NADPH to the corresponding hydroquinone that comproportionates with the large reservoir of quinone to initiate autoxidation. In the presence of microsomes, enzymatic one-electron reduction generates a semiquinone radical whose autoxidation with oxygen propagates the redox cycle. These results show the potential of some 2-(x'-chlorophenyl)-1, 4-benzoquinones to initiate the wasteful loss of NADPH.
McLean
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MR
Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536, USA.
Twaroski
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TP
Robertson
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LW
D000818:Animals; D016227:Benzoquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D002713:Chlorine / Q000378:metabolism; D004583:Electrons; D007425:Intracellular Membranes / Q000201:enzymology; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D009249:NADP / Q000378:metabolism*; D009285:Naphthoquinones / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000378:metabolism*; D011802:Quinidine / Q000031:analogs & derivatives / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D024483:Vitamin K 3
D016227:Benzoquinones; D009285:Naphthoquinones; D017382:Reactive Oxygen Species; D013481:Superoxides; C025232:semiquinone radicals; D002713:Chlorine; D009249:NADP; D024483:Vitamin K 3; C014486:hydroquinidine; D011078:Polychlorinated Biphenyls; D013482:Superoxide Dismutase; D011802:Quinidine; D010100:Oxygen