Arsenic induced mitochondrial DNA damage and altered mitochondrial oxidative function : Implications for genotoxic mechanisms in mammalian cells

Arsenic is a well-established human carcinogen that is chronically consumed in drinking water by millions of people worldwide. Recent evidence has suggested that arsenic is a genotoxic carcinogen. Furthermore, we have shown that mitochondria mediate the mutagenic effects of arsenic in mammalian cell...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2007-06, Vol.67 (11), p.5239-5247
Main Authors: PARTRIDGE, Michael A, HUANG, Sarah X. L, HERNANDEZ-ROSA, Evelyn, DAVIDSON, Mercy M, HEI, Tom K
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Arsenic - toxicity
Biological and medical sciences
Cricetinae
DNA Damage
DNA, Mitochondrial - drug effects
DNA, Mitochondrial - genetics
DNA, Mitochondrial - metabolism
Dose-Response Relationship, Drug
Electron Transport Complex IV - metabolism
Humans
Hybrid Cells
Medical sciences
Mitochondria - drug effects
Mitochondria - genetics
Mitochondria - metabolism
Mutagenicity Tests
Oxidation-Reduction
Oxygen Consumption - drug effects
Pharmacology. Drug treatments
Tumors
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Summary:Arsenic is a well-established human carcinogen that is chronically consumed in drinking water by millions of people worldwide. Recent evidence has suggested that arsenic is a genotoxic carcinogen. Furthermore, we have shown that mitochondria mediate the mutagenic effects of arsenic in mammalian cells, as arsenic did not induce nuclear mutations in mitochondrial DNA (mtDNA)-depleted cells. Using the human-hamster hybrid A(L) cells, we show here that arsenic alters mitochondrial function by decreasing cytochrome c oxidase function and oxygen consumption but increasing citrate synthase function. These alterations correlated with depletion in mtDNA copy number and increase in large heteroplasmic mtDNA deletions. In addition, mtDNA isolated periodically from cultures treated continuously with arsenic did not consistently display the same deletion pattern, indicating that the mitochondrial genome was subjected to repeated and continuous damage. These data support the theory that the mitochondria, and particularly mtDNA, are important targets of the mutagenic effects of arsenic in mammalian cells.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-07-0074