The Role of Protein Adduction in Toxic Neuropathies of Exogenous and Endogenous Origin

Abstract

The peripheral (axonal) neuropathy associated with repeated exposure to aliphatic and aromatic solvents that form protein-reactive γ-diketones shares some clinical and neuropathological features with certain metabolic neuropathies, including type-II diabetic neuropathy and uremic neuropathy, and with the largely sub-clinical nerve damage associated with old age. These conditions may be linked by metabolites that adduct and cross-link neuroproteins required for the maintenance of axonal transport and nerve fiber integrity in the peripheral and central nervous system.

Protein pyrrole adducts are associated with elevated glucose indices and clinical features of diabetic diffuse neuropathies

“…32 Although 2,5-HD is the ultimate neurotoxic metabolite of n-hexane, it is detectable (mean urinary 2,5-HD: 0.35-1.47 mg/L, median pyrrole adducts: 0.91-7.4 μM) in populations with no known occupational or environmental exposure to n-hexane or 2-hexanol. 10 The origin of endogenous 2,5-HD is unclear, but it may result from lipid oxidation, which also generates γ-ketoaldehydes. The commonly used method to detect urinary 2,5-HD measures both free 2,5-HD and 4,5-dihydroxy- 2-hexanone, 33 a reduction product of 3-HHD.…”

“… 8 Because aliphatic and aromatic γ‐diketones are established causes of distal symmetrical axonal neuropathy in humans and laboratory animals, 9 pyrrole‐protein reactions may be relevant to axonal neuropathies in diabetic states. 10 Here, we test the hypothesis that both plasma pyrrole adducts (PP) and adjusted urinary pyrrole adducts (aUP) are associated with glucose indices, that is, fasting blood glucose (FBG) and glycate hemoglobin A1c (HbA1c), and these associations are linked with some clinical features of DSPN. Our data are consistent with the hypothesis and set the stage for further clinical studies to examine the relationship between diabetic diffuse neuropathies and protein pyrrole adducts.…”

“…For example, 3‐hydroxy‐2,5‐hexanodione (3‐HHD), a γ‐diketone analogue generated from the nonenzymatic reaction of the AGE methylglyoxal, forms 3‐hydroxy‐pyrrolated adducts that are detectable in patients with diabetic ketosis 8 . Because aliphatic and aromatic γ‐diketones are established causes of distal symmetrical axonal neuropathy in humans and laboratory animals, 9 pyrrole‐protein reactions may be relevant to axonal neuropathies in diabetic states 10 . Here, we test the hypothesis that both plasma pyrrole adducts (PP) and adjusted urinary pyrrole adducts (aUP) are associated with glucose indices, that is, fasting blood glucose (FBG) and glycate hemoglobin A1c (HbA1c), and these associations are linked with some clinical features of DSPN.…”

The Glyoxalase System in Age-Related Diseases: Nutritional Intervention as Anti-Ageing Strategy

“…They found that this metabolic route involves a non-enzymatic aldol-reaction between MG and the ketone body acetoacetate, leading to 3-hydroxyhexane-2,5-dione, which is present in the blood of insulin-starved patients. Alternative pathways that might compensate the deficiency of glyoxalase system could potentially generate toxic molecules such as γ-diketones, which are associated with peripheral axonal degeneration and testicular injury [97,98].…”

Bottom-up proteomics analysis for adduction of the broad-spectrum herbicide atrazine to histone

“…Proteins can covalently adduct with xenobiotic compounds from exposure to endogenous or exogenous chemicals, such as drugs, pesticides, or their metabolites, at active amino acid residues [ 1 – 8 ]. Research over the past half century has demonstrated that these protein adducts might lead to multiple health issues, including cancer and immune system effects [ 1 , 5 , 7 , 9 – 13 ]. Therefore, identification of xenobiotics adducted to key proteins and identification of the sites of adduction within the protein are important to better understand the events underlying diseases and chemically induced adverse reactions.…”