Sülfür mustard toksisitesine karşı yeni moleküler stratejiler

Özet

Kullanılabilir kimyasal savaş ajanları içinde, hardal gazı olarak ta bilinen sülfür mustard (SM) kimyasal silah olarak yaygın şekilde kullanılmaktadır. Kapasite düşürücü bir ajan olarak SM toksisitesi, öldürücü kabiliyetinden çok daha tehlikelidir. Akut SM ile indüklenmiş hücresel toksisite hakkındaki bilinenlerin aksine, maalesef hardal gazının tek dozuna maruz kalınmasından yıllar sonra nasıl ciddi çoklu organ hasarı oluşturduğu açık değildir. Antioksidan ve antienflamatura ilaçları içeren bir kısım tedavi çeşitlemeleri ve diğerleri güvenilir olmayan sonular vermiştir. A variety of treatment modalities including antioxidants, anti-inflammatory drugs and others have resulted no promising results. Epigenetik aberasyonların mustard zehirlenmesinde etkisi üzerine bir deneme yaptık.

Abstract

Among the available chemical warfare agents, sulfur mustard (SM), also known as mustard gas, has been widely used chemical weapon. In our laboratory, we have shown that, acute toxicity of SM is related to reactive oxygen and nitrogen species, DNA damage, poly(ADP-ribose) polymerase activation and energy depletion within the affected cell. In spite of the knowledge about acute SM-induced cellular toxicity, unfortunately, it is not clear how mustard gas causes severe multi-organ damage years after even a single exposure. A variety of treatment modalities including antioxidants, anti-inflammatory drugs and others have resulted no promising results. We, therefore, made an attempt whether epigenetic aberrations may contribute to pathogenesis of mustard poisoning. The term epigenetic describes the study of inheritable alterations in gene expression that occur in the absence of changes in genome sequence. Therefore, epigenetic gene regulation requires molecular mechanisms that encode information in addition to the DNA base sequence and can be propagated through mitosis and meiosis. Our current understanding of epigenetic regulation of gene expression involves basically two classes of molecular mechanisms: histone modifications and DNA methylation. Preliminary evidence obtained from our laboratory reveals that exposure to mustards may not only cause nitro-oxidative stress and DNA (genetic) damage, but epigenetic perturbations as well. Epigenetic therapy is a new and rapidly developing field in pharmacology. Epigenetic drugs alone or in combination with conventional drugs may prove to be a significant advance over the conventional drugs used to treat both acute and delayed SM toxicity. Future studies are urgently needed to clarify the mechanism of delayed SM-induced toxicity and novel treatment modalities.