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COMPUTATIONAL INVESTIGATION OF CHEMICAL REACTIVITY IN RELATION TO BIOACTIVATION AND TOXICITY ACROSS CLASSES OF HALOORGANICS: BROMINATION VS. CHLORINATION
Citation:
Richard, A. M. AND P. Swartz. COMPUTATIONAL INVESTIGATION OF CHEMICAL REACTIVITY IN RELATION TO BIOACTIVATION AND TOXICITY ACROSS CLASSES OF HALOORGANICS: BROMINATION VS. CHLORINATION. Presented at Society of Toxicology, San Francisco, CA, March 25-29, 2001.
Description:
COMPUTATIONAL INVESTIGATION OF CHEMICAL REACTIVITY IN RELATION TO BIOACTIV A TION AND TOXICITY ACROSS CLASSES OF HALOORGANICS: BROMINATION VS. CHLORINATION.
Halogenation is a common feature of many classes of environmental contaminants, and often plays a crucial role in potentiating biological activation and toxicity through metabolism or formation of reactive intermediates. An example is in the area of water disinfection by-products, where a number of classes of small haloorganics (e.g. halomethanes, haloacetic acids, halohydroxyfuranones, etc.) contain chlorinated and brominated chemicals of concern for potential developmental or carcinogenic effects. A series of computational investigations are presented, spanning multiple classes of haloorganics, in which we have explored chemical reactivity hypotheses in relation to bioactivation mechanisms at appropriate levels of quantum mechanical theory. A structure-activity relationship (SAR) study of glutathione transferase zeta (GSTZ)-mediated conjugation for a series of a-haloacetic and halopropionic acids identified the energy of methyl sulfide attachment as a correlate with GSTZ substrate activity. For these compounds, we also simulated a carbonyl stretch to test the hypothesis that GSTZ catalytic function is enhanced by polarization of the acid carbonyl bond. Consistencies in the pattern of these changes, with both the SAR results and the measured biological activities, suggested a plausible chemical mechanism for GSTZ catalytic function. We have extended these studies to examine categories of bioactivation reactions (e.g. GSH conjugation, P-450 oxidation, radical dehalogenation) within other classes of haloorganics, such as the halomethanes, to determine differential effects of chlorination and bromination on potential modes of reactivity. The larger goal of these studies is to provide useful generalization with regard to these differential effects for classes of environmentally relevant haloorganics.
This abstract does not reflect EPA policy.