Medical Aspects of Chemical Warfare (2008) - The Black Vault

Vesicantsand other inhibitors of PADPRP can ameliorate thepathology developing in both living animal and cellularmodels. 36,37,43,44 Unfortunately, while niacinamidehas some beneficial actions, the protection it affordsis never complete and is limited in duration. 42,43 Noevidence currently shows activation of the hexosemonophosphate shunt following mustard exposure,but significant metabolic disruptions in human keratinocyteshave been reported after mustard exposure. 45Protease activity is increased in human cells exposedin vitro to mustard. 46–48Although many aspects of the PADPRP hypothesishave been verified, and there is good linkagebetween the proposed steps of this pathway andmustard-induced cytotoxicity, no direct correlationwith the full range of tissue pathologies seen followingmustard exposure has yet been established.Even though DNA is an important macromoleculartarget of mustard alkylation in the cell, several otherhypotheses of mustard toxicity have been developedthat are based on mustard’s reaction with other cellularcomponents. For a review of all such hypotheses, seeMedical Defense Against Mustard Gas: Toxic Mechanismsand Pharmacological Implications; only those undergoingactive investigation are discussed here. 31Reactions with GlutathioneThe second major hypothesis to explain the effectsof mustard proposes that the agent reacts with theintracellular free radical scavenger glutathione (GSH),thereby depleting it, resulting in a rapid inactivation ofsulfhydryl groups and the consequent loss of protectionagainst oxygen-derived free radicals, specificallythose causing lipid peroxidation. 49 In 1987 Orreniusand Nicotera established that menadione-induceddepletion of GSH resulted in loss of protein thiolsand inactivation of sulfhydryl-containing enzymes. 50Included in this class of thiol proteins are the calciumand magnesium adenosine triphosphatases, whichregulate calcium homeostasis. With the inactivation ofthe enzymes that control thiol proteins, intracellularcalcium levels would increase. High calcium levelswithin the cell trigger activation of protease, phospholipases,and endonucleases, which could give rise tothe breakdown of membranes, cytoskeleton, and DNAthat would result in cell death.One report suggested that this mechanism couldbe activated by mustards and might be the mechanismof mustard injury. 51 While several aspects of thethiol-calcium hypothesis (eg, release of arachidonicacid and decrease in membrane fluidity) have beenobserved in cell cultures following sulfur mustardexposure, no definitive studies have drawn an associationbetween calcium disruptions and mustardinducedpathology. 52Another proposed consequence of the assumeddepletion of GSH following mustard exposure is lipidperoxidation. 53,54 According to this hypothesis, depletionof GSH allows the formation of oxygen-derivedfree radicals. The oxidizing compounds thus formedwould react with membrane phospholipids to formlipid peroxides that could, in turn, lead to membranealterations, changes in membrane fluidity, and eventualbreakdown of cellular membranes.As previously mentioned, studies have shownchanges in membrane fluidity following sulfur mustardexposure. 52 In addition, in 1989 Elsayed and colleaguesdemonstrated the presence of lipid peroxidation indicatorsin the tissue of mice exposed to subcutaneousbutyl mustard. 55 However, as with the thiol-calciumhypothesis, no studies have directly linked lipid peroxidationwith mustard-induced injury.MetabolismAs the first step in any of the mustard injury theories,mustard cyclizes to a sulfonium electrophilic center.This highly reactive moiety, in turn, combines withpeptides, proteins, DNA, or other substances. Aftera few minutes in a biological milieu, intact mustardis no longer present; the reactive electrophile has attachedto another molecule and is no longer reactive.The rapidity of this reaction also means that, within afew minutes, mustard has started to cause tissue damage.The clinical relevance is that intact mustard or itsreactive metabolic product is not present in tissue orbiological fluids, including blister fluid, a few minutesafter the exposure; however, clothing, hair, and skinsurfaces may still be contaminated hours later.Several studies support the observation that intactor active mustard is not present in tissue or biologicalfluids after a few minutes. 31–33,56 Occluding theblood supply to areas of the intestinal tract or toselected bone marrow for a few minutes protectedthese organs from the effects of a lethal amount ofintravenously administered mustard. Approximately85% of S-labeled mustard disappeared from the bloodof humans after several minutes, and the half-life forintravenously administered mustard to disappearfrom the blood of piglets was about 2 minutes. 37,57,58Mustard blister fluid did not produce a reactionwhen instilled into the eyes of animals or humans oronto the skin of humans. 59,60 A continuing outbreakof smaller vesicles near a source of blister fluid isprobably the result of these areas having received anadditional exposure and not from contamination bythe blister fluid. 59,61265