ToxSci Advance Access originally published online on May 22, 2007
Toxicological Sciences 2007 98(2):561-570; doi:10.1093/toxsci/kfm127
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Neurotoxic Mechanisms of Electrophilic Type-2 Alkenes: Soft–Soft Interactions Described by Quantum Mechanical Parameters
* Department of Anesthesiology, Albert Einstein College of Medicine, Montefiore Medical Center, 111 E. 210th St, Bronx, New York 10467
Department of Chemistry, Iona College, New Rochelle, New York 10804
1 To whom correspondence should be addressed at Montefiore Medical Center, Moses Research Tower - 7, 111 E. 210th St, Bronx, NY 10467. Fax: (718) 515-4903. E-mail: lopachin{at}aecom.yu.edu.
Received March 7, 2007; accepted May 7, 2007
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Abstract |
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Conjugated Type-2 alkenes, such as acrylamide (ACR), are soft electrophiles that produce neurotoxicity by forming adducts with soft nucleophilic sulfhydryl groups on proteins. Soft–soft interactions are governed by frontier molecular orbital characteristics and can be defined by quantum mechanical parameters such as softness (
) and chemical potential (µ). The neurotoxic potency of ACR is likely related to the rate of adduct formation, which is reflected in values of . Correspondingly, differences in µ, the ability of a nucleophile to transfer electrons to an electrophile, could determine protein targets of these chemicals. Here, and µ were calculated for a series of structurally similar Type-2 alkenes and their potential sulfhydryl targets. Results show that N-ethylmaleimide, acrolein and methylvinyl ketone were softer electrophiles than methyl acrylate or ACR. Softness () was closely correlated to corresponding second-order rate constants (k2) for electrophile reactions with sulfhydryl groups on N-acetyl-L-cysteine (NAC). The rank order of softness was also directly related to neurotoxic potency as determined by impairment of synaptosomal function and sulfhydryl loss. Calculations of µ showed that the thiolate state of several cysteine analogs was the preferred nucleophilic target of alkene electrophiles. In addition, µ was directly related to the thiolate rate constant (k) for the reaction of the Type-2 alkenes with the cysteine compounds. Finally, in accordance with respective µ values, we found that NAC, but not N-acetyl-L-lysine, protected synaptosomes from toxicity. These findings suggest that the neurotoxicity of ACR and its conjugated alkene analogs is related to electrophilic softness and that the thiolate state of cysteine residues is the corresponding adduct target.
Key Words: distal axonopathy; acrylamide; acrolein; Type-2 alkenes; adduct formation; nerve terminal; neurotoxicity.
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