Protein Adduct Formation as a Molecular Mechanism in Neurotoxicity

Abstract

Chemicals that cause nerve injury and neurological deficits are a structurally diverse group. For the majority, the corresponding molecular mechanisms of neurotoxicity are poorly understood. Many toxicants (e.g., hepatotoxicants) of other organ systems and/or their oxidative metabolites have been identified as electrophiles and will react with cellular proteins by covalently binding nucleophilic amino acid residues. Cellular toxicity occurs when adduct formation disrupts protein structure and/or function, which secondarily causes damage to submembrane organelles, metabolic pathways, or cytological processes. Since many neurotoxicants are also electrophiles, the corresponding pathophysiological mechanism might involve protein adduction. In this review, we will summarize the principles of covalent bond formation that govern reactions between xenobiotic electrophiles and biological nucleophiles. Because a neurotoxicant can form adducts with multiple nucleophilic residues on proteins, the challenge is to identify the mechanistically important adduct. In this regard, it is now recognized that despite widespread chemical adduction of tissue proteins, neurotoxicity can be mediated through binding of specific target nucleophiles in key neuronal proteins. Acrylamide and 2,5-hexanedione are prototypical neurotoxicants that presumably act through the formation of protein adducts. To illustrate both the promise and the difficulty of adduct research, these electrophilic chemicals will be discussed with respect to covalent bond formation, suspected protein sites of adduction, and proposed mechanisms of neurotoxicity. The goals of future investigations are to identify and quantify specific protein adducts that play a causal role in the generation of neurotoxicity induced by electrophilic neurotoxicants. This is a challenging but critical objective that will be facilitated by recent advances in proteomic methodologies.

Increased Risk for Obesity and Diabetes with Neurodegeneration in Developing Countries

“…Sirt 1 is closely involved in with chromatin modification and protection of neurons from genotoxic stress with the involvement of DNA repair enzymes and repair of double strand breaks in damaged chromatin structure [131,132]. In liver and brain cells with low Sirt 1 activity electrophiles from xenobiotic metabolism react with micro ribonucleic acid (RNA) [133][134][135] or by covalent binding to nucleophillic centres in cellular protein and DNA [136][137][138][139]. Adduct formation disrupts DNA or protein structure with damage to the nucleus and various subcellular organelles [128,130,140] such as the ER and mitochondria with metabolic alterations.…”

Electrophysiological Studies of Shoemakers Exposed to Sub‐TLV Levels of n‐hexane

“…The neurotoxic effects of HEX are related to 2,5-HD 11,15) , an active γ -diketone that is the only neurotoxic metabolite of HEX. Recent studies have shown that axon atrophy is the morphological hallmark of γ -diketone neuropathy 16,17) and that regardless of exposure rate (100−400 mg/kg/day), it is an early consequence of 2,5-HD neurotoxicity and a necessary event in the pathophysiological process that leads to γ -diketone neurological toxicity 18) . Use of the urinary concentration of free 2,5-HD has been proposed for biological monitoring of workers exposed to HEX 19−23) , and the American Conference of Governmental Industrial Hygienists (ACGIH) proposed a value of 0.4 mg/l as the reference value for it 20) .…”

Towards a Deeper Understanding of the Mechanisms of Interaction between Acrylamide and Key Body-Fluid Thiols

“…The epoxide group of GA makes it more electrophilic than AA and can bind with DNA. GA-DNA adducts have been isolated in animal studies and is proposed to be the compound responsible for the genotoxicity of AA [13,14]. Studies have shown that AA will preferentially bind with proteins, free amino acids, and thiols, than with DNA [12,13].…”