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Oxidative DNA adducts after Cu2+-mediated activation of dihydroxy PCBs: Role of reactive oxygen species
Journal article   Open access   Peer reviewed

Oxidative DNA adducts after Cu2+-mediated activation of dihydroxy PCBs: Role of reactive oxygen species

Wendy A Spencer, Hans-Joachim Lehmler, Larry W Robertson and Ramesh C Gupta
Free radical biology & medicine, Vol.46(10), pp.1346-1352
05/2009
DOI: 10.1016/j.freeradbiomed.2009.02.005
PMID: 19233261
url
http://doi.org/10.1016/j.freeradbiomed.2009.02.005View
Open Access

Abstract

Polychlorinated biphenyls (PCBs) are toxic industrial chemicals, complete carcinogens, and efficacious tumor promoters. However, the mechanism(s) of PCB-mediated carcinogenicity remains largely undefined. One likely pathway by which these agents may play a role in carcinogenesis is the generation of oxidative DNA damage by redox cycling of dihydroxylated PCB metabolites. We have now employed a new 32P-postlabeling system to examine novel oxidative DNA lesions induced by Cu2+-mediated activation of PCB metabolites. 32P postlabeling of DNA incubated with various PCB metabolites resulted in over a dozen novel polar oxidative DNA adducts that were chromatographically similar for all active agents. The most potent metabolites tested were the hydroquinones (hydroxyl groups arranged para to each other), yielding polar oxidative adduct levels ranging from 55 to 142 adducts/106 nucleotides. PCB catechols, or ortho-dihydroxy metabolites, were up to 40% less active than their corresponding hydroquinone congeners, whereas monohydroxylated and quinone metabolites did not produce detectable oxidative damage over that of vehicle. With the exception of 2,4,5-Cl-2′,5′-dihydroxybiphenyl, this oxidative DNA damage seemed to be inversely related to chlorine content: no chlorine ≈ mono- > di- > trichlorinated metabolites. Importantly, copper, but not iron, was essential for activation of the PCB metabolites to these polar oxidative DNA adducts, because in its absence or in the presence of the Cu+-specific scavenger bathocuproine, no adducts were detected. Intervention studies with known reactive oxygen species (ROS) modifiers suggested that H2O2, singlet oxygen, hydroxyl radical, and superoxide may also be involved in this PCB-mediated oxidative DNA damage. These data indicate a mechanistic role for several ROS, in addition to copper, in PCB-induced DNA damage and provide further support for oxidative DNA damage in PCB-mediated carcinogenesis.

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