In vitro oxidation of the hydrolysis product of sulfur mustard, 2,2?-thiobis-ethanol, by mammalian alcohol dehydrogenase

Abstract

The mechanism of vesication from sulfur mustard remains unknown in spite of 80 years of investigation. We recently reported sulfur mustard–related inhibition of one or more protein (serine/threonine) phosphatases in tissue cytosol in vitro, suggesting a mechanism common to other vesicants such as cantharidin and Lewisite. Our investigation showed that this inhibition was related to the concentration of 2,2′‐thiobis‐ethanol (thiodiglycol), the hydrolysis product of sulfur mustard, rather than to the concentration of mustard itself. Related work showed an increase in the rate of NAD (but not NADP) reduction upon the addition of thiodiglycol to mouse liver cytosol. This result provided evidence that metabolism beyond thiodiglycol may be contributing to protein phosphatase inhibition. This observation indicated that metabolism involving one or more dehydrogenases may be necessary to produce the ultimate inhibitor of the protein phosphatases. We report here that thiodiglycol is a substrate for horse liver alcohol dehydrogenase (Km = 3.68 ± 0.45 mM and Vmax = 0.22 ± 0.01 μmol min−1 mg protein−1) and for pyridine nucleotide‐linked enzymes in mouse liver and human skin cytosol. The alcohol dehydrogenase‐specific inhibitor 4‐methylpyrazole inhibited the oxidation of thiodiglycol by the pure horse liver enzyme as well as by the enzymes in human skin and mouse liver cytosol, indicating that the activity in the tissue preparations is also alcohol dehydrogenase. © 1998 John Wiley & Sons, Inc. J Biochem Mol Toxicol 12: 361–369, 1998

Neglected role of hydrogen sulfide in sulfur mustard poisoning: Keap1 S-sulfhydration and subsequent Nrf2 pathway activation

“…SM also induces lipid peroxidation and protein oxidation. The former generates highly reactive electrophilic lipid peroxidation end products, whereas the latter modifies the functional activity of enzymes and structural proteins 43 , 44 . Therefore, SM toxicity may be the result of direct damage induced by oxidative stress.…”

New insights into the biodegradation of thiodiglycol, the hydrolysis product of Yperite (sulfur mustard gas)

“…To test the involvement of an alcohol dehydrogenase activity in the initial breakdown on TDG, the strains were grown in 100 ml bottles containing 20 ml of ME medium containing 10 mmol l −1 of TDG in both the presence and absence of 1 mmol l −1 4‐methylpyrazole (Sigma‐Aldrich), an inhibitor of alcohol dehydrogenase (Brimfield et al. 1998).…”

Free Radical Production and Oxidative Stress in Lung Tissue of Patients Exposed to Sulfur Mustard: An Overview of Cellular and Molecular Mechanisms

“…It is now elucidated that SM can accelerate OS through induction of ROS generation and decrease of antioxidant capacities . The resulted OS may damage DNA, leading to chromosome instability, altered expression of some genes, and genetic mutations that are associated with cell death and lung damage. , SM may also induce protein and lipid oxidation, which can modify the functional activity of various enzymes, structural proteins, and cell membranes …”