Metabolic Activation of PCBs to Quinones:  Reactivity toward Nitrogen and Sulfur Nucleophiles and Influence of Superoxide Dismutase

Abstract

Polychlorinated biphenyls (PCBs) may undergo cytochrome P-450-catalyzed hydroxylations to form chlorinated dihydroxybiphenyl metabolites. When the hydroxyl groups are ortho or para to each other, oxidation to a quinone may be catalyzed by peroxidases present within the cell. In order to study the reactivity of PCB-derived quinones, selected chlorophenyl 1,2- and 1,4-benzoquinones were synthesized and characterized, including their reduction potentials against a saturated calomel electrode. Two quinones, 4-(4'-chlorophenyl)-1,2-, and 4-(3',4'-dichlorophenyl)-1,2-benzoquinone, were obtained via the oxidation of the corresponding dihydroxybiphenyls with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. Six 1,4-benzoquinones were synthesized via the Meerwein arylation: 2-(2'-chlorophenyl)-1,4-, 2-(3'-chlorophenyl)-1,4-, 2-(4'-chlorophenyl)-1,4-, 2-(2',5'-dichlorophenyl)-1,4-, 2-(3',4'-dichlorophenyl)-1,4-, and 2-(3',5'-dichlorophenyl)-1,4-benzoquinone. As a model study, the rate of reactivity of 2-(4'-chlorophenyl)-1,4-benzoquinone toward the nitrogen nucleophiles glycine, L-arginine, L-histidine- and L-lysine was determined under pseudo-first-order conditions at pH 7.4. The rate constants ranged from 0.45 to 0.75 min-1 M-1. Higher rates were obtained under conditions of higher pH. Two reaction products were identified as the 5- and 6-ring addition products in the ratio of 1:4. In contrast, the reaction of 2-(4'-chlorophenyl)-1,4-benzoquinone with the sulfur nucleophiles glutathione or N-acetyl-L-cysteine was instantaneous. The major product of the reaction of glutathione with 2-(4'-chlorophenyl)-1,4-benzoquinone was also the 6-ring addition product. The hydroquinone thioether could be enzymatically reoxidized to the quinone thioether. Also, the influence of atmospheric oxygen and superoxide dismutase on the rates of the following horseradish peroxidase/H2O2-catalyzed oxidations was investigated: 3,4-dichloro-2',5'-dihydroxybiphenyl to 2-(3',4'-dichlorophenyl)-1,4-benzoquinone and 3,4-dichloro-3',4'-dihydroxybiphenyl to 4-(3',4'-dichlorophenyl)-1,2-benzoquinone. While the presence or absence of atmospheric oxygen did not alter the rates of the oxidation reactions, the presence of superoxide dismutase significantly increased the rates of both oxidation reactions, having the greater effect on the oxidation of the 1,4-hydroquinone. These data show that PCB-derived quinones react with both nitrogen and sulfur nucleophiles of the cell and may explain, in part, the toxic effects of individual PCBs and PCB formulations, such as glutathione depletion, oxidative stress, and cell death.

Sequestration of a highly reactive intermediate in an evolving pathway for degradation of pentachlorophenol

“…A similar reactivity profile has been observed for the benzoquinones of polychlorinated biphenyls (24). Reactions with nucleotides are even Reaction mixtures contained 100 μM PCP, 50 μM NADPH, and 50 μM NADH, except where indicated.…”

Understanding the human health effects of chemical mixtures.

“…Marchlewicz et al (226) demonstrated that many spermatozoa of leadexposed rats had abnormal reactions of antioxidant enzymes in the midpiece, suggesting that impairment of free-radical scavenging enzymes may be an important factor in lead-induced ROS formation. Although no studies report oxidative stress in sperm following exposure to PCBs, the ortho-and para-hydroxylated metabolite of PCBs can be converted to quinones by peroxidases (227). The quinones can undergo redox cycling to produce ROS, and 8-OHdG is formed in an in vitro system of calf thymus DNA, lactoperoxidase, and 3,4-dichloro-2´,5´-dichlorobiphenyl (228).…”

Mutagenicity of 3-methylcholanthrene, PCB3, and 4-OH-PCB3 in the lung of transgenic BigBlue® rats

“…Arene oxides can undergo further biotransformation to a mono-hydroxylated form and further to di-hydroxylated metabolites, which may be oxidized to quinones (McLean et al, 1996a). The arene oxide and quinone metabolites are electrophiles and can bind to nucleophilic sites in amino acids, proteins, and DNA (Amaro et al, 1996;Arif et al, 2003;McLean et al, 1996b;Pereg et al, 2002;Pereg et al, 2001;Srinivasan et al, 2001;Srinivasan et al, 2002;Tampal et al, 2003). Also, during this oxidative metabolism reactive oxygen species (ROS) can be generated, which produce 8-oxo-dG and DNA strand breaks (McLean et al, 1998;Oakley et al, 1996;Srinivasan et al, 2001).…”