ToxSci Advance Access published online on October 5, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl127
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1 Department of Anesthesiology, Albert Einstein College of Medicine, Montefiore Medical Center, 111 E. 210th st., Bronx, NY 10467
* To whom correspondence should be addressed. Acrylamide (ACR) is a conjugated Type-2 alkene that produces synaptic toxicity presumably by sulfhydryl adduction. The
Received July 12, 2006
Accepted September 23, 2006
Neurotoxicology
Structure-Toxicity Analysis of Type-2 Alkenes: in Vitro Neurotoxicity
Richard M. LoPachin 1 *, David S. Barber 2, Brian C. Geohagen 1, Terrence Gavin 3, Deke He 1, and Soma Das 1
2 Center for Environmental and Human Toxicology, University of Florida, Building 471, Mowry Rd., Gainesville, FL 32611-0885
3 Department of Chemistry, Iona College, New Rochelle, NY 10804
Richard M. LoPachin, E-mail: lopachin{at}aecom.yu.edu
Abstract 
,
-unsaturated carbonyl of ACR is a soft electrophile and, therefore, adduction of nucleophilic thiol groups could occur through a conjugate (Michael) addition reaction. To address the mechanism of thiol adduct formation and corresponding neurotoxicological importance, we defined structure-toxicity relationships among a series of conjugated Type-2 alkenes (1µM-10mM), which included acrolein and methylvinyl ketone. Results show that exposure of rat striatal synaptosomes to these chemicals produced parallel, concentration-dependent neurotoxic effects that were correlated to loss of free sulfhydryl groups. Although differences in relative potency were evident, all conjugated analogs tested were equiefficacious with respect to maximal neurotoxicity achieved. In contrast, non-conjugated alkene or aldehyde congeners did not cause synaptosomal dysfunction or sulfhydryl loss. Acrolein and other ,-unsaturated carbonyls are bifunctional (electrophilic reactivity at the C-1 and C-3 positions) and could produce in vitro neurotoxicity by forming protein cross-links rather than thiol monoadducts. Immunoblot analysis detected slower migrating, presumably derivatized, synaptosomal proteins only at very high acrolein concentrations (
25mM). Exposure of synaptosomes to high concentrations of ACR (1M), N-ethylmaleimide (10mM) and methyl vinyl ketone (100mM) did not alter the gel migration of synaptosomal proteins. Furthermore, hydralazine (1 mM), which blocks the formation of protein cross-links, did not affect in vitro acrolein neurotoxicity. Thus, Type-2 conjugated alkenes produced synaptosomal toxicity that was linked to a loss of thiol content. This is consistent with our hypothesis that the mechanism of ACR neurotoxicity involves formation of Michael adducts with protein sulfhydryl groups.
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