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Superfund Grantee Speaks on "The King of Poisons"

By Eddy Ball
November 2007

Because the problem is not just arsenic, but also the element's metabolites, Aposhian told the audience,
Because the problem is not just arsenic, but also the element's metabolites, Aposhian told the audience, "I don't know of another cancer system that is as complicated as the arsenic cancer system." (Photo courtesy of Steve McCaw)

NIEHS Superfund Basic Research Program grantee Vasken Aposhian, Ph.D., enlightened and entertained a standing-room-only audience in Rodbell Auditorium on October 17 with his talk on arsenic. Titled "The King of Poisons, the Poison of Kings and the Bane of Investigators," Aposhian's Superfund Distinguished Lecture focused on what he considers to be the three milestones in arsenic research since the 1980s, when Superfund support revived investigations into the biochemistry and health risks of the ubiquitous element.

Aposhian, whose lecture was hosted by Superfund Acting Director Claudia Thompson, Ph.D., is currently a professor in the Department of Molecular and Cellular Biology at the University of Arizona. In the course of a career spanning over fifty years, he has distinguished himself in the area of molecular mechanisms of toxic metals.

"He is truly an internationally recognized expert in the area of metal intoxication," Thompson said of his numerous invited lectures and extensive travel overseas.

The Superfund Program, which is set to celebrate its 20th anniversary in December, was founded in 1987 - the same year that the National Science Foundation (NSF) turned down Aposhian's request for funding to study arsenic. According to Aposhian, an NSF reviewer commented, "It's a very exotic subject, but everyone knows that everything is known about arsenic. There's nothing else to be done."

Not long afterward, with Superfund support, Aposhian's group and others set out to prove the reviewer wrong. In the intervening 20 years, Aposhian observed, this research has helped millions of people worldwide better appreciate the health threat posed by arsenic in the water they drink, the food they eat and the air they breathe.

A favored means of murder called the "inheritance drug" in France, arsenic was undetectable in vivo until the 1830s, and many questions about the element were still unanswered more than 150 years afterwards. The first milestone in arsenic research that Aposhian discussed involves recent insights into arsenic metabolism and the SNPs that can interfere with detoxification of the metabolites formed by biotransformation of the element. These developments are important because, as Aposhian observed, "Inorganic arsenic toxicity is relatively low compared to the toxicity of [the downstream metabolites] MMA(III) and DMA(III)."

According to Aposhian, understanding what enzyme is responsible for the methylation of arsenic species in the human still needs further investigative effort. Arsenic methylation is an important biotransformation pathway in humans and animals that is likely characterized by some enzyme redundancy. The three proposed pathways - involving rabbit-type methyltransferases, CYT 19 and glutathione compounds - are probably all involved, but Aposhian cautioned that until an enzyme can be purified from surgically removed human tissue, the question will remain unanswered.

Aposhian pointed to what he considers the two most important arsenic papers published in the past 25 years. The first, from the Columbia group headed by Joe Graziano, Ph.D. Exit NIEHS, found a significant association between arsenic in drinking water and reduced intellectual function among children in Bangladesh. In the second, an investigative team led by NIEHS Research Pharmacologist Michael Waalkes, Ph.D. Exit NIEHS, reported on a rodent model of inorganic arsenic carcinogenesis in liver, ovary, lung and adrenal glands.

The improved analytical techniques that are now available have made possible identification of the metabolite MMA(III) for the first time in human urine. The Aposhian group's recent acquisition of rapid and sensitive technology has helped the team carry out automated high-throughput speciation analysis.

Although major breakthroughs have taken place in arsenic research and in the development of advanced proteomic methodology, such as Differential Gel Electrophoresis (DIGE), Aposhian concluded that there remain many questions to be answered, ranging from sample collection details to validation procedures. He called for more DIGE global discovery studies, more investigations into cytokines and second messengers, and more studies using surgically removed human tissue.

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