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Arsenic Biomethylation Required for Oxidative DNA Damage

By Laura Hall
December 2009

Michael Waalkes, Ph.D.
Michael Waalkes
(Photo courtesy of Steve McCaw)

Ronald Mason, Ph.D.
Ron Mason
(Photo courtesy of Steve McCaw)

According to,Exit NIEHS inorganic arsenic occurs naturally in the earth's crust and results from man-made activities such as mining, smelting and coal-fired power plants. Inorganic arsenic is known to be carcinogenic to humans and is a common contaminate in drinking water. NIEHS researchers have found that biomethylation of arsenic compounds, previously considered to be a detoxification mechanism, actually appears to cause oxidative DNA damage and to increase arsenic carcinogenicity. The findings were published in an online article titled "Requirement of Arsenic Biomethylation for Oxidative DNA Damge," which recently appeared online in the Journal of the National Cancer Institute.

Michael Waalkes, Ph.D., of the National Cancer Institute, is currently on detail at NIEHS. Waalkes and several other colleagues, including Ronald Mason, Ph.D. a principal investigator in the NIEHS Laboratory of Pharmacology, compared methylation-competent and methylation-deficient cell lines exposed to arsenic. Exposure of methylation-competent cells, but not methylation-deficient cells, was followed by a sharp rise in oxidative damage. After the peak of oxidative DNA damage (ODD), methylation-competent cells acquired the in vitro characteristics of cancer cells. The methylation-deficient cells exhibited the same characteristics, but at a much later time.

Biomethylation is a mechanism of metabolizing arsenic in the body whereby one or more methyl groups is attached to the inorganic arsenic. Methylation-competent cells have this biomethylation ability. The in vitro characteristics of cancer, the cancer phenotype, used in this study included enhanced cellular invasiveness, cell proliferation, and activity of certain enzymes. These attributes are all commonly increased in cells that develop cancer from arsenic exposure.

The authors treated arsenic exposed methylation-competent rat liver epithelial cells with selenite, an arsenic biomethylation inhibitor. Selenite treatment abolished arsenic-induced ODD and the in vitro cancer phenotype, which indicated that biomethylation, not inorganic arsenicals, are likely to be key factors for ODD formation.

Oxidative DNA radicals that cause ODD were detected using immuno-spin trapping (IST), a method that converts the DNA radicals induced by reactive oxygen species, which normally last only milliseconds or less, to stable DNA-nitrone adducts that last months or years. The DNA is then extracted from the cells and immuno-chemically quantified. IST, a methodology developed by Mason at NIEHS, avoids the artifacts and indirect quantitation found in other methods used to measure DNA radicals.

A human urothelial cell line, UROtsa, stably transduced with mouse arsenite methyltransferase (As3mt), an enzyme which adds a methyl group to inorganic arsenical, made the cells arsenic methylation-competent. These cells showed more ODD and developed the cancer phenotype more quickly than the parent cell line that was methylation-deficient. Mutations of the human version of this gene are known to affect arsenical methylation.

Mice have been engineered to lack the As3mt gene. "Although inorganic arsenicals have not yet been tested for carcinogenic effects in these genetically altered mice, this clearly should be a high priority," the authors write.

Citation: Kojima C, Ramirez DC, Tokar EJ, Himeno S, Drobna Z, Syblo M, Mason, RP, Waalkes MP. ( NIEHS 2009. Requirement of arsenic biomethylation for oxidative DNA damage. J Natl Cancer Inst Advance Access published November 23, 2009, doi:10.1093/jnci/djp414

(Laura Hall is a biologist in the NIEHS Laboratory of Pharmacology currently on detail as a writer for the Environmental Factor.)

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