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화학적 , 대사적 산화반응중 생성되는 S - oxide 를 이용한 O - ethyl S - methyl ethylphosphonothioate(1) 의 독성 기작에 관한 연구
허장현,Fukuto, T R,한대성 한국환경농학회 1991 한국환경농학회지 Vol.10 No.2
O,S-dialkyl alkylphosphonothioates 계열 유기인제 농약의 체내 작용기작을 이해하기 위하여 model 화합물 (1), O-ethyl S-methyl ethylphosphonothioate [LD_(50) (rat, oral) 4.6㎎/㎏ : K_i(bovine erythrocyte acetylcholinesterase) 303 M^(-1)min^(-1)]이 선정되었다. 이 유기인계 화합물들은 체내에서 活性化 과정을 겪으면서 毒性을 발현하는 것으로 假說되어져 왔다. 생체 내 mixed function oxidases에 의한 산화 활성화 과정을 化學的으로 재현하기 위하여 두 종류의 유기산화제 즉, meta-chloroperoxybenzoic acid와 monoperoxyphthalic acid가 사용되었고, 代謝的 산화를 재현하기 위하여 쥐 肝에서 추출한 microsomal oxidation system을 이용한 in vitro 산화반응이 시도되었다. 산화반응 중간생성물인 S-oxide의 존재가 전구물질(1)의 가설적 산화 반응경로를 통해서 간접적으로나마 충분히 확인 되어질 수 있었다. 더욱이 ethanol을 이용한 trapping실험에서 불안정한 산화중간물질인 S-oxide가 강한 phosphorylating agent라는 것이 확인되어, 전구물질 (1)로부터 산화반응을 거치면서 생성된 이 중간물질이 체내 신경전달에 중요한 역할을 하는 acetylcholinesterase를 phosphorylation하게 되고, 결국 이런 활성화 과정을 통해 이 계열의 화합물들이 독성을 발휘하는 것으로 이해될 수 있었다. O-ethyl S-methyl ethylphosphonothioate [LD_(50) (rat, oral) 4.6㎎/㎏ : K_i(bovine erythrocyte acetylcholinesterase) 303 M^(-1min-1)] was selected as a model compound to study the mode of action of O, S-dialkyl alkylphosphonothioates which have been hypothesized to be toxic via a bioactivation process. Two chemical oxidants, meta-chloroperoxybenzoic acid and monoperoxyphthalic acid, and rat liver microsomal oxidases were used to mimic the action of mixed function oxidases on the model compound. The formation of S-oxide, a very unstable active intermediate, was proposed based on the identification of metabolic products. Furthermore, a trapping experiment with ethanol showed that the unstable intermediate S-oxide had the ability to phosphorylate acetylcholinesterase which is an important enzyme in nerve systems. The S-oxide intermediates are presumed to be responsible for the toxicity of O,S-dialkyl alkylphosphonothioates.
Comparing the Chemical Biology of NO and HNO
Wilmarie Flores-Santana,Christopher Switzer,Lisa A. Ridnour,Debashree Basudhar,Daniele Mancardi,Sonia Donzelli,Douglas D. Thomas,Katrina M. Miranda,Jon M. Fukuto,David A. Wink 대한약학회 2009 Archives of Pharmacal Research Vol.32 No.8
For the past couple of decades nitric oxide (NO) and nitroxyl (HNO) have been extensively studied due to the important role they play in many physiological and/or pharmacological processes. Many researchers have reported important signaling pathways as well as mechanisms of action of these species, showing direct and indirect effects depending on the environment. Both NO and HNO can react with, among others, metals, proteins, thiols and heme proteins via unique and distinct chemistry leading to improvement of some clinical conditions. Understanding the basic chemistry of NO and HNO and distinguishing their mechanisms of action as well as methods of detection are crucial for understanding the current and potential clinical applications. In this review, we summarize some of the most important findings regarding NO and HNO chemistry, revealing some of the possible mechanisms of their beneficial actions.