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Mentor: Jonathan Doorn, PhD
Year Entered Into Program: 2006-2011
PhD Institution: Case Western Reserve Univ., Cleveland, OH
Molinate is a thiocarbamate herbicide, commonly used as a pre-emergent in rice patty fields, which has been shown to cause neurotoxicity. Molinate undergoes oxidation to molinate sulfoxide and is further oxidized to molinate sulfone, an electrophile reactive toward thiols. Previous work demonstrated a decrease in aldehyde dehydrogenase (ALDH) activity in rats treated with molinate. These findings suggest the sulfone metabolite of molinate, and perhaps the sulfoxide metabolite, to be an inhibitor of ALDH, potentially modifying the active-site cysteine. ALDH is an enzyme important in the catabolism of many neurotransmitters, and inhibition of these catabolic processes may lead to the accumulation of neurotoxic metabolites such as 3,4-dihydroxyphenylacetaldehyde (DOPAL). The hypothesis of my current research is molinate and both metabolites inhibit ALDH through modification of the active-site cysteine, and molinate sulfone is the most potent inhibitor. To test this hypothesis, molinate sulfoxide and molinate sulfone were synthesized, and various model systems were used, including rat brain ALDH, rat striatal mitochondria, synaptosomes, and human recombinant ALDH. The enzyme activity was monitored in each of these model systems and the relative potency of each inhibitor determined. Preliminary results demonstrate molinate, molinate sulfone, and molinate sulfoxide inhibit ALDH activity, causing an increase of the endogenous neurotoxin, DOPAL, and molinate sulfone is the most potent ALDH inhibitor. Future work will include elucidating the mechanism of ALDH inhibition for each of these inhibitors, and analyzing the effects of these inhibitors on dopaminergic PC6-3 cells.
Gagan, E.M., Hull, M.W., Schultz, T.W., Poch, G., Dawson, D.A.: Time dependence in mixture toxicity with soft electrophiles: 1. Combined effects of selected SN2- and SNAr- reactive agents with a nonpolar narcotic. Archives of Environmental and Contamination Toxicology, 52(3):283-293, 2007. PMID: 17253098
Roberts, R.A., Laskin, D.L., Smith, C.V., Robertson, F.M., Allen, E.M., Doorn, J.A., and Slikker, W.: Nitrative and Oxidative Stress in Toxicology and Disease. Toxicological Sciences, 112(1):4-16, 2009. PMCID: PMC2769059
E.M.G. Allen, D.G.R. Anderson, V.R. Florang, T.D. Hurley, and J.A. Doorn (2010). Relative Inhibitory Potency of Molinate and Metabolites with Aldehyde Dehydrogenase: Implications for the Mechanism of Enzyme Inhibition. Chemical Research in Toxicology, 23(11):1843-1850, 2010. PMID: 20954713
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