رسالة جامعية
Effects of chloroacetaldehyde on 2-chloroethanol intoxication and its related mechanisms
| العنوان: | Effects of chloroacetaldehyde on 2-chloroethanol intoxication and its related mechanisms |
|---|---|
| العنوان البديل: | 氯乙醛在2-氯乙醇中毒所扮演的角色及作用機制之探討 |
| المؤلفون: | Yng-Tay Chen, 陳瀅太 |
| مرشدي الرسالة: | 廖俊旺 |
| سنة النشر: | 2009 |
| المجموعة: | National Digital Library of Theses and Dissertations in Taiwan |
| الوصف: | 98 2-Chloroethanol (2-CE) is widely used industrial solvent. In Taiwan, farmers apply 2-CE on grapevines to accelerate grape growth, a practice that some cases have caused poisoning in humans. Thus there is strong interest in identifying antidotes to 2-CE. The aim of this study was contained with four parts. Part I, this study examines the protective role in 2-CE intoxicated rats. Alcohol dehydrogenase and glutathione were hypothesized to be important in the metabolism of 2-chloroethanol. This study used fomepizole, an alcohol dehydrogenase inhibitor, and chemicals that affected glutathione metabolism to study 2-CE toxicity. Notably, fomepizole 5 mg/kg significantly increased median lethal dose (LD50) of 2-CE from 65.1 mg/kg to 180 mg/kg, and reduced the production of a potential toxic metabolite chloroacetaldehyde (CAA) in animal plasma. In contrast, disulfiram (DSF), an aldehyde dehydrogenase inhibitor, increased the toxicity of 2-CE on the lethality in rats. Additional or pretreatment with N-acetylcysteine (NAC) and fomepizole significantly reduced plasma CAA concentrations. Fomepizole also significantly reduced 2-CE inhibited glutathione activity. Otherwise, pretreatment with NAC for four days followed by co-treatment with fomepizole significantly decreased formation of the metabolic CAA. These results indicated that its catalytic enzyme might play a vital role during 2-CE intoxication, and the combination of fomepizole and NAC could be a protective role in cases of acute 2-CE intoxication. Part II, severe hypotension is one of main toxic signs during intoxication. Calcium ion modulation is considered to be an important role of vasorelaxation. The aim of this study is to evaluate either 2-CE or its main metabolite, CAA, possible cause of hypotension, by using isolated rat aortic rings. Results revealed that 2-CE caused a weakly relaxation in the phenylephrine (PE) pre-induced endothelium-intact aortic rings. However, its metabolite, CAA induced vasorelaxation and showed dose dependency in endothelium-intact and -denuded aortic rings. The half inhibitory concentration (IC50) of 2-CE exceeded 50 mM; meanwhile, the IC50 values of CAA in the endothelium-intact and -denuded aortic rings were 3.3 and 2.7 mM, respectively. The CAA-induced relaxation could be significantly attenuated by adding calcium (CaCl2) and various Ca2+ channel blockers, dantrolene, nifedipine, and NiCl2. Nifedipine presents the most strong inhibition effect among the calcium blockers. In conclusion, it is suggested that the hypotension effect of 2-CE intoxicated cases may be mainly mediated by its metabolite CAA, and calcium channels are partially involved inducing the vasorelaxation. Part III, cardiovascular effects have often been found in 2-CE-intoxicated humans, but the mechanism by which 2-CE elicits cardiovascular toxicity is not clear. In this study an in vitro isolated rat atrium model was used to examine the cardiovascular toxicity of 2-CE. Results indicated that 2-CE inhibited tension in the isolated rat left atria. In addition, CAA caused significant tension inhibition and contracture in the isolated rat left atria. Nifedipine, an L-type calcium channel blocker, decreased CAA-induced tension inhibition and contracture. 2-Chloroethanol did not cause tension arrest in isolated rat right atria, but CAA did. Meanwhile, neuronal nitric oxide synthase (nNOS) was significantly expressed in 2-CE-intoxicated rat brain and isolated aortic rings. Furthermore, atrial nNOS and calmodulin (CaM) had significantly greater expression in the CAA group than the 2-CE group. Pretreatment with nifedipine decreased CAA-induced nNOS and CaM expression. These results indicate that 2-CE cardiovascular toxicity might be due to its metabolite CAA and that nifedipine is protective against nNOS-triggered cardiovascular toxicity. Part IV, 2-CE, and its metabolite, CAA was a well known mutagenicity agent. The genotoixic study of CAA had not been studied. Chronic occupation injury might escape the focus of 2-CE intoxication. In this study, we were using the in vitro and in vivo genotoxicity tests to examine the mutagenicity of 2-CE and CAA. First, the Ames test showed the 2-CE and CAA did not induce TA98 and TA100 Salmonella typhimurium strains reversions nearby the bacterial toxicity. Second, 2-CE did not induce chromosome aberrations formation by using Chinese ovary hamster cells, but CAA did induce chromosome aberrations formation at chromosome type gap aberration only after S9 activation. Third, 2-CE did not induce mice peripheral blood micronucleus formation, but high dosage of 2-CE (i.p. 1/2 LD50) would induce micronucleus formation. Otherwise, CAA induced micronucleus formation at low and high dosage (1/8 to 1/2 LD50). These results indicated that CAA is a genotoxic agent; however the mechanisms of CAA mutagenesis need further study. |
| Original Identifier: | 098NCHU5541002 |
| نوع الوثيقة: | 學位論文 ; thesis |
| وصف الملف: | 93 |
| الإتاحة: | http://ndltd.ncl.edu.tw/handle/50909816917672812827Test |
| رقم الانضمام: | edsndl.TW.098NCHU5541002 |
| قاعدة البيانات: | Networked Digital Library of Theses & Dissertations |
| الوصف غير متاح. |