Molecular targets against mustard toxicity: implication of cell surface receptors, peroxynitrite production, and PARP activation.
Despite many years of research into chemical warfare agents, cytotoxic mechanisms induced by mustards are not well understood. Reactive oxygen and nitrogen species (ROS and RNS) are likely to be involved in chemical warfare agents induced toxicity. These species lead to lipid peroxidation, protein oxidation, and DNA injury, and trigger many pathophysiological processes that harm the organism. In this article, several steps of pathophysiological mechanisms and possible ways of protection against chemical warfare agents have been discussed. In summary, pathogenesis of mustard toxicity is explained by three steps: (1) mustard binds target cell surface receptor, (2) activates intracellular ROS and RNS leading to peroxynitrite (ONOO(-)) production, and (3) the increased ONOO(-) level damages organic molecules (lipids, proteins, and DNA) leading to poly(adenosine diphosphate-ribose) polymerase (PARP) activation. Therefore, protection against mustard toxicity could also be performed in these ways: (1) blocking of cell surface receptor, (2) inhibiting the ONOO(-) production or scavenging the ONOO(-) produced, and (3) inhibiting the PARP, activated by ONOO(-) and hydroxyl radical (OH(*)) induced DNA damage. As conclusion, to be really effective, treatment against mustards must take all molecular mechanisms of cytotoxicity into account. Combination of several individual potent agents, each blocking one of the toxic mechanisms induced by mustards, would be interesting. Therefore, variations of combination of cell membrane receptor blockers, antioxidants, nitric oxide synthase inhibitors, ONOO(-) scavengers, and PARP inhibitors should be investigated.
Department of Physiology, Gulhane Military Medical Academy, 06018 Etlik/Ankara, Turkey.
Ahmet
A
Korkmaz
Hakan
H
Yaren
Turgut
T
Topal
Sukru
S
Oter
D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D002619:Chemical Warfare Agents / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009150:Mustard Compounds / Q000633:toxicity*; D009151:Mustard Gas / Q000633:toxicity; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009588:Nitrogen Mustard Compounds / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects*; D030421:Peroxynitrous Acid / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000187:drug effects*
D000931:Antidotes; D000975:Antioxidants; D002619:Chemical Warfare Agents; D004791:Enzyme Inhibitors; D009150:Mustard Compounds; D009588:Nitrogen Mustard Compounds; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D011065:Poly(ADP-ribose) Polymerases; D009151:Mustard Gas