Dissertation/Thesis Abstract

Selenium in the detoxification of arsenic: Mechanisms and clinical efficacy
by La Porte, Paul Francois, Ph.D., The University of Chicago, 2011, 215; 3472891
Abstract (Summary)

it was proposed that antagonistic effects noted between selenium and arsenic might be leveraged through the dispensation of selenium dietary supplements in arsenic-afflicted regions. (A full discussion of arsenic toxicity, selenium in human health, and prior knowledge of selenium-arsenic interactions can be found in Chapter I).

In this context, this dissertation addresses both (1) the clinical efficacy of using dietary selenium supplementation to mitigate arsenic toxicity, as well as (2) the mechanism that underpins the observed antagonism between the two elements.

In tandem with the clinical trial, experiments were conducted to determine whether the aforementioned metabolite discovered by our colleagues in rabbits is (1) formed in humans, (2) formed environmentally and clinically relevant concentrations of arsenic and selenium, (3) formed in significant quantities in proportion to the total burden of arsenic in the bloodstream, and (4) shunted towards the liver and intestines in a pattern consistent with a hepatobiliary excretion. In the first major experiment, a subset of patients involved in the clinical trial volunteered for a pharmacokinetic experiment to detect and characterize the formation of the [(GS)2AsSe] compound. These patients consumed home drinking water naturally contaminated with arsenic, in addition to selenium supplements. Blood specimens at multiple time points were analyzed by X-ray absorption spectroscopy [XAS]. For the first time, [(GS)2AsSe] was identified in human patients, and was noted to peak between 20 and 60 minutes after dosing. It was also found that the metabolite was the major species of arsenic and selenium in the blood following selenium intake, while the metabolite was negligible or undetectable in patients under control conditions. In the second major experiment, hamsters that had been intoxicated with arsenic and selenium showed a shunting of arsenic and selenium in a 1:1 ratio towards the liver, gallbladder, and small intestines. Taken together, these experiments showed that the [(GS)2AsSe] compound is formed in the blood of human patients at clinically relevant arsenic exposure and selenium dosing levels, and that the formation of the [(GS)2AsSe] compound and its hepatobiliary excretion is the major metabolic pathway when selenium is used to counter arsenic toxicity. (A full discussion of the design, execution, and results of these experiments can be found in Chapter II).

To assess selenium's clinical efficacy, the author designed and coordinated a Phase III, double-blind, placebo-controlled, randomized, 48-week long clinical trial that was conducted with 819 adults and adolescents from an arsenic-afflicted region of Bangladesh. The primary trial endpoint was the measurement of changes in arsenical melanosis as a surrogate measure for the health effects of chronic arsenic poisoning, particularly arsenical cancers. Secondary endpoints included changes in levels of blood and urinary arsenic as measures of the body's arsenic load. After successful execution of the trial with high levels of adherence, no effects due to treatment assignment were observed in either the primary or the secondary endpoints. Adjustments for a variety of covariates also did not elucidate any effect in patients who had received selenium treatment in comparison to those who had received placebo. (A full discussion of the clinical trial's design, execution and results can be found in Chapter III).

The combined results of the clinical trial and the human and animal experiments broadly indicate that (1) selenium-arsenic antagonism is mediated in humans by the hepatobiliary-mediated excretion of the metabolite [(GS)2AsSe], but that (2) this phenomena cannot be leveraged to observable clinical benefit under the constraints and conditions of the SETAC trial. It remains possible that longer-term treatment, the use of differential dosing, and the use of alternative endpoints might identify a clinical benefit to selenium supplementation in arsenicosis patients. (Abstract shortened by UMI.)

Indexing (document details)
Advisor: Ahsan, Habibul, Dolan, M. Eileen
Commitee: George, Graham N., Grdina, David, Greene, Geoffrey L., Halpern, Howard, Marshall, James R., Spallholz, Julian E.
School: The University of Chicago
Department: Cancer Biology
School Location: United States -- Illinois
Source: DAI-B 72/12, Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Molecular biology, Molecular chemistry, Medicine, Oncology
Keywords: Arsenic, Bangladesh, Cancer, Chelation, Detoxification, Selenium
Publication Number: 3472891
ISBN: 9781124868479
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