Kovacic P, Cooksy A
Department of Chemistry, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182-1030, USA.
Med Hypotheses. 2005;64(1):104-11. doi: 10.1016/j.mehy.2004.03.048.
The mechanism of nicotine toxicity is not completely delineated. Considerable evidence points to involvement of oxidative stress (OS), reactive oxygen species, lipid peroxidation, DNA damage, and beneficial effect of antioxidants. Previously, a suggestion was advanced for participation of iminium metabolites which might operate, via electron transfer (ET) with redox cycling, to produce radical entities. The conjugated iminium functionality is one of the less well-known ET types. The cationic metabolites arise from several routes, including oxidation of nicotine itself, and protonation of myosmine which originates from nornicotine via demethylation of nicotine. Reduction potentials, which are in the range amenable to ET in vivo, lend credence to the theoretical framework. An alternate metabolic route entails hydrolysis of nicotine iminium to an open-chain ketoamine that, in turn, undergoes nitrosation to form a toxic nitrosamine. Subsequently, the nitrosamine serves as a DNA alkylator which can also generate conjugated iminiums by attack on certain nitrogens of DNA bases. During the past 14 years, the hypothesis has enjoyed substantial support. Increasing evidence points to a role for OS in toxicity by nicotine entailing major body organs, including the lung, cardiovascular system, central nervous system, liver, kidney, testes, ovary, pancreas, and esophagus. The mechanism of addiction is also addressed based on interaction of iminiums with normal electron transport chains or electrical phenomena in the brain. The process might occur with or without participation of reactive oxygen species. Evidence indicates that free radicals are widely involved in cell signaling entailing redox processes in the categories of ion transport, neuromodulation, and transcription. Low levels of radicals appear to participate since high concentrations are associated with toxicity. Various possibilities for future work based on the hypothetical approach are addressed, including some that may have practical utility in relation to health improvement, toxicity, and addiction. Insight should be gained from computational studies on the energetics of electron uptake by metabolic iminiums, and on stability of the resultant delocalized radicals. Additional large-scale investigations of antioxidant effects are needed in order to resolve prior conflicting reports. Other proposals are based on interference with metabolism to iminiums and nitrosamines, and destruction of harmful metabolites. Since the iminium entities are proposed to play crucial, adverse roles, it would be worthwhile to explore them with regard to receptors, physiological activities, possible generation of reactive oxygen species, and effect of antioxidants.
尼古丁毒性的机制尚未完全阐明。大量证据表明氧化应激（OS）、活性氧、脂质过氧化、DNA损伤以及抗氧化剂的有益作用都与之相关。此前，有人提出亚胺离子代谢产物可能参与其中，它们可能通过电子转移（ET）和氧化还原循环产生自由基实体。共轭亚胺离子功能是一种不太为人所知的电子转移类型。阳离子代谢产物有多种产生途径，包括尼古丁本身的氧化，以及降烟碱经尼古丁去甲基化产生的麦斯明的质子化。体内适合电子转移的还原电位范围为这一理论框架提供了可信度。另一条代谢途径是尼古丁亚胺离子水解为开链酮胺，然后酮胺发生亚硝化形成有毒的亚硝胺。随后，亚硝胺作为DNA烷化剂，也可通过攻击DNA碱基的某些氮原子生成共轭亚胺离子。在过去14年里，这一假说得到了大量支持。越来越多的证据表明，氧化应激在尼古丁对包括肺、心血管系统、中枢神经系统、肝脏、肾脏、睾丸、卵巢、胰腺和食管在内的主要身体器官的毒性作用中发挥作用。成瘾机制也基于亚胺离子与大脑中正常电子传输链或电现象的相互作用进行了探讨。这个过程可能在有或没有活性氧参与的情况下发生。有证据表明自由基广泛参与细胞信号传导，涉及离子运输、神经调节和转录等氧化还原过程。似乎是低水平的自由基参与其中，因为高浓度的自由基与毒性有关。基于这一假说方法探讨了未来工作的各种可能性，包括一些可能对改善健康、毒性和成瘾具有实际应用价值的可能性。应该从关于代谢亚胺离子摄取电子的能量学以及所得离域自由基稳定性的计算研究中获得见解。为了解决先前相互矛盾的报告，需要进行更多大规模的抗氧化作用研究。其他建议基于对亚胺离子和亚硝胺代谢的干扰以及有害代谢产物的破坏。由于亚胺离子实体被认为起着关键的不良作用，因此有必要从受体、生理活性、活性氧的可能产生以及抗氧化剂的作用等方面对其进行探索。
