Mustard gas

Although HD and HN2 are recognized as carcinogens, short-term, limited exposure shows no association with the development of either pulmonary or skin tumors except if scars develop at the site of cutaneous exposure.[1,16,20] Repeat exposure to HD and HN2 is associated with an increased incidence of airway and cutaneous malignancies.[20] While HD is lipophilic, its biotransformation is governed by its reaction in aqueous media. Intramolecular cyclization to form an electrophilic ethylene episulfonium intermediate leads to the toxic sulfur mustard products.[1,16] The availability of electrons within molecules determines the avidity of compounds for the electrophilic products produced by HD hydrolysis.[6,25] Functional groups in molecules, which increase electron availability, decrease reactivity and this explains the highly competitive factors of a number of molecules, especially sulfhydrylcontaining compounds. Alkylating agents are defined by their capability of replacing a proton in another molecule by an alkyl cation.[7] Although the rate of alkylation by HD is similar to the rate of hydrolysis by HD, alkylation products exhibit great stability. HD and HN2 are bifunctional alkylating agents that can crosslink DNA as well as produce single strand DNA breaks.[18,20,26] Other macromolecules including RNA and proteins can be alkylated, because DNA functions as a single unit during cell replication and division, its alkylation has a much greater impact on the short-term survival of the cell as well as for possible later transformation.[1,16] HD alkylation has some specificity, and the most neutrophilic sites are most susceptible in the absence of steric effects.[20,26] In DNA, this preferentially occurs in runs of guanines, which are present in only l.3% of the human genome.[26] However, a significant number of oncogenes and viral oncogenes are rich in guanine.[26] This may explain the response of some tumors, particularly some virally induced tumors, to this class of drug as well as the development secondary malignancies after exposure to mustards.[26] The specificity in DNA binding may also play a role in the specific structural proteins, adhesion molecules, cytokines, and/or enzymes are affected. Because interstrand crosslinks are major inhibitors of DNA synthesis, but have comparatively minor effects on total protein and RNA synthesis, they primarily target rapidly proliferating cells. Thus, transiently amplifying cells, mainly in the basal cell layer (BCL) of the epidermis, would be expected to be most sensitive to these agents. Stem cells, which need to maintain a low cytoplasmic/nuclear ratio, are also sensitive to these agents because the more marked inhibition of nuclear DNA synthesis to inhibition of cytoplasmic proteins and RNA results in unbalanced growth with increases in the cytoplasmic/nuclear ratio. The spectrum of molecular mechanism involved in HD-induced epidermal cell injury and death is still far from clear in spite of the fact that areas of DNA alkylation and intra-strand crosslinks can be predicted. For most of the last century, work has focused on activation of the enzyme poly(adenosine diphosphate-ribose)polymerase (PADPRP) following DNA alkylation, with the induction of DNA repair of strand breaks or apoptosis.[1,16] PADPRP utilizes nicotinamide adenine dinucleotide (NAD+) as a substrate in enzymatic reactions with a number of nuclear proteins. With depletion of NAD+ there is inhibition of glycolysis and stimulation of the NAD phosphate-dependent hexose monophosphate shunt. Increased activity of the hexose monophosphate shunt results in increased proteases, which are proposed to play a role in the HD-induced cellular damage and blister formation.[1] Inhibitors of PADPRP provide little protection from HD-induced epidermal damage, and they may actually increase the long-term carcinogenic potential of HD.[1,20] It has also been proposed that a significant portion of the toxicity of HD is secondary to ES or ROS with depletion of cellular detoxifying thiols including glutathione. Thiols are one of the body's main defense mechanisms against ES and ROS. Protein sulfhydryls are then exposed to ES and OS.[15] Sulfhydryl groups on a number of proteins affect cellular function, the most critical of which are enzymes that maintain cellular Ca2+ homeostasis.[1,20] Loss of Ca2+ homeostasis leads to disruption of microfilamentous proteins that maintain the cytoskeletal and structural integrity of the cell, and/or induction of apoptosis or necrosis through activation of endonucleases, proteases, and/or phospholipases, which can induce DNA and/or membrane damage.[1,20] ROS, dependent on the level, may increase ceramides leading to apoptosis/necrosis and/or lead to genomic damage.[1,20] Clinically, hyperpigmentation is a frequent sequel after exposure to HD even in the absence of blister and subsequent ulcer formation. This predisposition to hyperpigmentation also supports depletion of glutathione and other intracellular thiols, since their depletion leads to tyrosinase activity and favors eumelanogenesis.[3,20] Melanogenesis may also be enhanced by DNA repair enzymes which are upregulated by agents which damage DNA.[20] HD and HN2 are potent alkylating agents, and although less significant than their reactions with DNA, their reactive products are capable of reacting with a host of compounds whose integrity is vital to the normal functioning of living cells. They react with carboxyl groups, primary, secondary, and tertiary aliphatic amino groups, heterocyclic nitrogen atoms, sulfide groups, and organic and inorganic phosphate compounds to form in most cases very stable compounds.l[9,27,28] Enzymes and cytokines are also induced by these reactions, and the direct and secondary effects of mustard agents on inflammatory cells contribute to the clinical disease.[19,27,28]