Production of DNA strand breaks in vitro and reactive oxygen species in vitro and in HL-60 cells by PCB metabolites

Anandi Srinivasan; Hans-Joachim Lehmler; Larry W Robertson; Gabriele Ludewig

doi:10.1093/toxsci/60.1.92

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Production of DNA strand breaks in vitro and reactive oxygen species in vitro and in HL-60 cells by PCB metabolites

Journal article

Open access

Peer reviewed

Production of DNA strand breaks in vitro and reactive oxygen species in vitro and in HL-60 cells by PCB metabolites

Anandi Srinivasan, Hans-Joachim Lehmler, Larry W Robertson and Gabriele Ludewig

Toxicological sciences, Vol.60(1), pp.92-102

03/2001

DOI: 10.1093/toxsci/60.1.92

PMID: 11222876

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Abstract

PCBs are industrial chemicals that continue to contaminate our environment. They cause various toxic effects in animals and in exposed human populations. The mechanisms of toxicity, however, are not completely understood. PCBs are metabolized by cytochromes P450 to mono- and dihydroxylated compounds. Dihydroxy-PCBs can potentially be oxidized to the corresponding quinones. We hypothesized that reactive oxygen species (ROS) are produced by redox reactions of PCB metabolites. We tested several synthetic dihydroxy- and quinoid-PCBs with 1-3 chlorines for their potential to produce ROS in vitro and in HL-60 human leukemia cells, and DNA strand breaks in vitro. All dihydroxy-PCBs tested produced superoxide. The quinones generated superoxide only in the presence of GSH, probably during the autoxidation of the glutathione conjugates. We observed increased superoxide production with decreasing halogenation. Incubation of dihydroxy-PCBs or PCB quinones + GSH with plasmid DNA resulted in DNA strand break induction in the presence of Cu(II). Tests with various ROS scavengers indicated that hydroxyl radicals and singlet oxygen are likely involved in this strand break induction. Finally, dihydroxy- and quinoid PCBs also produced ROS in HL-60 cells in a dose- and time-dependent manner. We conclude that dihydroxylated PCBs, and PCB quinones after reaction with GSH, produce superoxide and other ROS both in vitro and in HL-60 cells, and oxidative DNA damage in the form of DNA strand breaks in vitro. The reactions seen in vitro and in cells may well be a predictor of the toxicity of PCBs in animals.

DNA Damage - drug effects

Cell Survival - drug effects

Reactive Oxygen Species - metabolism

Oxidation-Reduction

Humans

HL-60 Cells - drug effects

Environmental Pollutants - metabolism

Polychlorinated Biphenyls - metabolism

Hydroquinones - metabolism

HL-60 Cells - metabolism

Dose-Response Relationship, Drug

Hydroquinones - toxicity

HL-60 Cells - cytology

Polychlorinated Biphenyls - toxicity

Quinones - toxicity

Environmental Pollutants - toxicity

Quinones - metabolism

Details

Title: Subtitle: Production of DNA strand breaks in vitro and reactive oxygen species in vitro and in HL-60 cells by PCB metabolites
Creators: Anandi Srinivasan - Graduate Center for Toxicology, 306 Health Sciences Research Building, University of Kentucky Medical Center, Lexington, Kentucky 40536-0305, USA
Hans-Joachim Lehmler
Larry W Robertson
Gabriele Ludewig
Resource Type: Journal article
Publication Details: Toxicological sciences, Vol.60(1), pp.92-102
DOI: 10.1093/toxsci/60.1.92
PMID: 11222876
NLM abbreviation: Toxicol Sci
ISSN: 1096-6080
eISSN: 1096-0929
Publisher: United States
Grant note: P42 ES 07380 / NIEHS NIH HHS
Language: English
Date published: 03/2001
Academic Unit: Occupational and Environmental Health; Iowa Neuroscience Institute
Record Identifier: 9983997353702771

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