Hathway D E
Hatfield College, University of Durham.
Biol Rev Camb Philos Soc. 2000 Feb;75(1):95-127. doi: 10.1017/s0006323199005447.
Some six or so physiological systems, essential to normal mammalian life, are involved in poisoning; an intoxication that causes severe injury to any one of them could be life threatening. Reversible chemical reactions showing Scatchard-type binding are exemplified by CO, CN- and cyclodiene neurotoxin insecticide intoxications, and by antigen-antibody complex formation. Haemoglobin (Hb) molecular biology accounts for the allosteric co-operativity and other characteristics of CO poisoning, CN- acts as a powerful cytochrome oxidase inhibitor, and antigen binding in a deep antibody cleft between two domains equipped with epitopes for antigen-binding groups explains hapten-specific immune reactions. Covalent chemical reactions with second-order (SN2) kinetics characterize Hg and Cd poisonings, the reactions of organophosphates and phosphonates with acetylcholinesterase and neurotoxic esterase and the reaction sequence whereby Paraquat accepts electrons and generates superoxide under aerobic conditions. Indirect carcinogens require cytochrome P450 activation to form DNA adducts in target-organ DNA and cause cancer, but a battery of detoxifying enzymes clustered with the P450 system must be overcome. Thus, S-metabolism competes ineffectively with target DNA for reactive vinyl chloride (VC) metabolites, epoxide hydrolase is important to the metabolism and carcinogenicity of alfatoxins and polycyclic aromatic hydrocarbons (benzo[a]pyrene, etc.), and the non-toxic 2-naphthylhydroxylamine N-glucuronide acts as a transport form in 2-naphthylamine bladder cancer. VC liver-cancer pathogenesis is explicable in terms of the presence of the glutathione S-transferase detoxifying system in hepatocytes and its absence from the fibroblastic elements, and of the VC concentrations reaching the liver by different administrative routes. In VC carcinogenicity, chemical reactions give imidazo-cyclization products with nucleoside residues of target DNA, and in benzene leukaemia, Z,Z-muconaldehyde forms cyclic products containing a pyrrole residue linked to purine. Increased HbCO concentrations reduce the O2-carrying capacity of the blood, and the changed shape of the O2-Hb dissociation curve parallels disturbance in O2 unloading. CN- acts on electron transport and paralyses respiration. In telodrin poisoning, preconvulsive glutamine formation abstracts tricarboxylic acid intermediates incommensurately with normal cerebral respiration. Antigen-antibody complexing depletes the antibody titre, available against infection. At high doses of Cd, Cd-thionein filtered through the kidneys is reabsorbed and tubular lesions produced. Some organophosphate insecticides promote irreversible acetylcholinesterase phosphorylation and blockade nerve function, and others react with neurotoxic esterase to cause delayed neuropathy. The evidence for Paraquat pulmonary poisoning suggests a radical mechanism involving three interrelated cyclic reaction stages. The action of N- and O8 (O substituent in 6-position of the purine) demethylases explains deletion mechanisms for DNA-alkyl adducts. DNA-directed synthesis in the presence of ultimate carcinogens provides for an estimation of misincorporations, which implicate the same transversions as those found by direct mutagenicity testing. Chemical carcinogens recognize tissue-sensitive cells and modify their heritable genetic complement. Oncoproteins encoded by activated oncogenes signal the transformation of normal cells into cancer cells. The importance of the H-ras oncogene and p53 tumour-suppressor gene is stressed. Antidotal action is analysed; for example, parenteral glutamine administration to telodrin-intoxicated rats restores the depleted cerebral glutamate level and prevents seizures. Glutamate acts as anticonvulsant in petit mal epilepsy. In general, therefore, the reaction of the toxicant-related substance with the relevant target-tissue macromolecule accounts for the biochemical/biological events at a cellular level a
大约六个左右对正常哺乳动物生命至关重要的生理系统会参与中毒过程；任何一个系统受到严重损伤的中毒都可能危及生命。显示Scatchard型结合的可逆化学反应以一氧化碳、氰化物和环二烯神经毒素杀虫剂中毒以及抗原 - 抗体复合物形成为例。血红蛋白（Hb）分子生物学解释了一氧化碳中毒的变构协同作用及其他特征，氰化物是一种强大的细胞色素氧化酶抑制剂，抗原在配备有抗原结合基团表位的两个结构域之间的深抗体裂隙中结合解释了半抗原特异性免疫反应。具有二级（SN2）动力学的共价化学反应是汞和镉中毒、有机磷酸酯和膦酸酯与乙酰胆碱酯酶和神经毒性酯酶的反应以及百草枯在有氧条件下接受电子并产生超氧化物的反应序列的特征。间接致癌物需要细胞色素P450激活才能在靶器官DNA中形成DNA加合物并导致癌症，但必须克服与P450系统聚集在一起的一系列解毒酶。因此，硫代谢与靶DNA竞争氯乙烯（VC）反应性代谢物的能力较弱，环氧水解酶对黄曲霉毒素和多环芳烃（苯并[a]芘等）的代谢和致癌性很重要，无毒的2 - 萘基羟胺N - 葡萄糖醛酸苷在2 - 萘胺膀胱癌中作为转运形式。氯乙烯肝癌的发病机制可以从肝细胞中存在谷胱甘肽S - 转移酶解毒系统而纤维母细胞成分中不存在以及通过不同给药途径到达肝脏的氯乙烯浓度来解释。在氯乙烯致癌性方面，化学反应会与靶DNA的核苷残基形成咪唑环化产物，在苯致白血病方面，Z，Z - 粘康醛会形成含有与嘌呤相连的吡咯残基的环状产物。血红蛋白一氧化碳（HbCO）浓度升高会降低血液携带氧气的能力，氧合血红蛋白解离曲线形状的改变与氧气卸载的紊乱平行。氰化物作用于电子传递并使呼吸麻痹。在异狄氏剂中毒时，惊厥前谷氨酰胺的形成会不相称地提取三羧酸中间体，与正常脑呼吸不一致。抗原 - 抗体复合会消耗抗感染的抗体滴度。高剂量镉时，通过肾脏滤过的镉 - 硫蛋白会被重吸收并产生肾小管损伤。一些有机磷杀虫剂会促进不可逆的乙酰胆碱酯酶磷酸化并阻断神经功能，其他一些则与神经毒性酯酶反应导致迟发性神经病变。百草枯肺部中毒的证据表明存在一种涉及三个相互关联的循环反应阶段的自由基机制。N - 去甲基酶和O8（嘌呤6位的O取代基）去甲基酶的作用解释了DNA - 烷基加合物的缺失机制。在最终致癌物存在下的DNA定向合成可用于估计错配掺入情况，这与直接诱变测试中发现的相同颠换有关。化学致癌物识别组织敏感细胞并改变其可遗传的基因组成。由活化癌基因编码的癌蛋白会发出信号，将正常细胞转化为癌细胞。强调了H - ras癌基因和p53肿瘤抑制基因的重要性。分析了解毒作用；例如，给异狄氏剂中毒的大鼠肠胃外注射谷氨酰胺可恢复耗尽的脑谷氨酸水平并预防惊厥。谷氨酸在失神性癫痫中起抗惊厥作用。因此，一般来说，毒物相关物质与相关靶组织大分子反应解释了细胞水平的生化/生物学事件。
