Arsenic is a toxic metalloid and is ubiquitous in our environment. In ancient cultures it was valued as a poison and today is becoming an increasing public health problem. Chronic arsenic exposure has a broad range of toxic effects including cancer. Currently millions of people are exposed to higher levels of arsenic in their food and drinking water than is considered safe by the World Health Organization. Although arsenic metabolism is not completely understood, it is known that inorganic arsenate is reduced to arsenite which can then be methylated and excreted in the urine. It is also known that some arsenic is retained in the body, presumably by binding to cellular proteins. To better understand how arsenic is metabolized, our approach was to identify and characterize proteins that are involved in arsenic metabolism. Using biochemical approaches we demonstrated that arsenate reductase activity from human liver was purine nucleoside phosphorylase (PNP). We were able to demonstrate that calf spleen PNP has arsenate reductase activity in vitro in the presence of inosine and dihydrolipoic acid, and that the reaction exhibits Michaelis-Menten kinetics. This identifies an enzymatic route for arsenate reduction. We also demonstrate that ferritin, an iron storage protein containing phosphate, can bind arsenic both in vitro and in vivo. In addition, we demonstrate that ferritin can oxidize arsenite to arsenate, and then interact with arsenate as it does with phosphate. We also establish that arsenate can inhibit ferritin's ability to store iron in vitro. Our results combined with data reported by others, suggest that DNA damage and enzyme inactivation associated with arsenic challenge may occur via reactive oxygen species generated by arsenic-iron redox reactions in ferritin, and that iron may augment arsenic toxicity. The interaction between ferritin and arsenate has two important implications. First, it suggests that iron exposure may be an important parameter to examine in epidemiological studies of arsenic sensitivity. Second, it suggests that iron chelation therapy might be beneficial in conjunction with arsenic chelation therapy for patients suffering from acute arsenic poisoning.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/280379 |
| Date | January 2003 |
| Creators | Radabaugh, Timothy |
| Contributors | Parker, Roy R. |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | en_US |
| Detected Language | English |
| Type | text, Dissertation-Reproduction (electronic) |
| Rights | Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. |
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