Castagnoli N, Rimoldi J M, Bloomquist J, Castagnoli K P
Department of Chemistry and Entomology, Virginia Tech, Blacksburg 24061-0212, USA.
Chem Res Toxicol. 1997 Sep;10(9):924-40. doi: 10.1021/tx970096j.
A major theme explored in this review is the MAO-and cytochrome P450-catalyzed alpha-carbon oxidations of selected cyclic tertiary amines to give iminium metabolites that undergo further chemical modifications to form known or potentially toxic products. The most dramatic illustration of this type of bioactivation process is the conversion of the parkinsonian-inducing neurotoxin MPTP (23) by brain MAO-B to the iminium (dihydropyridinium) metabolite 24 which is oxidized further to the pyridinium species MPP+ (25). The selective destruction of nigrostriatal neurons by MPP+ is dependent on a unique sequence of events (transport into the nerve terminals by the dopamine transporter, localization in the inner mitochondrial membrane by electromotive forces, and inhibition of complex I of the mitochondrial electron transport chain) that, fortunately, are unlikely to be encountered with many substances. A second example of a well-documented metabolic bioactivation sequence involves the highly toxic pyrrolizidine alkaloids (102). These compounds undergo cytochrome P450-catalyzed alpha-carbon oxidation which converts the 3-pyrrolinyl moiety present in the parent alkaloids into a pyrrolyl-containing metabolite (105). The presence of labile functional groups results in the spontaneous conversion of 105 to reactive electrophilic products (106 and 108) that undergo Michael addition reactions with nucleophiles on biomacromolecules leading to a variety of toxic outcomes. Less clearly defined are the potential contributions to neurodegenerative processes that may be mediated by low-level, long term exposure to less potent toxins. Examples of potential proneurotoxins are the endogenously formed tetrahydroisoquinolines (such as 40-50) and tetrahydro-beta-carbolines (such as 54) that may be biotransformed to neurotoxic isoquinolinium (such as 51) and beta-carbolinium (such as 52) species in the brain. A similar argument can be made for 4-piperidinols (compounds that are at the same oxidation state as the tetrahydropyridines) which may be metabolized via iminium intermediates to amino enols that spontaneously convert to dihydropyridinium species and hence to pyridinium metabolites (67-->68-->69-->70-->71, Scheme 10). This type of reaction sequence has been well documented with the parkinsonian-inducing neuroleptic agent haloperidol (72) which is metabolized in humans, baboons, and rodents to the pyridinium species HPP+ (75), a potent inhibitor of mitochondrial respiration. Finally, an appreciation of the alpha-carbon oxidations of fully reduced azacycles such as (S)-nicotine (61) and phencyclidine (82) to chemically reactive metabolites that form covalent adducts with proteins, including the enzymes that are responsible for their formation, may prove of toxicological importance when attempting to account for the effects of chronic abuse of these potent drugs.1
本综述探讨的一个主要主题是，单胺氧化酶和细胞色素P450催化特定环状叔胺的α-碳氧化，生成亚胺代谢物，这些代谢物会进一步发生化学修饰，形成已知的或潜在有毒的产物。这种生物活化过程最显著的例子是，帕金森病诱导神经毒素MPTP（23）被脑内单胺氧化酶B转化为亚胺（二氢吡啶鎓）代谢物24，该代谢物进一步氧化为吡啶鎓物质MPP⁺（25）。MPP⁺对黑质纹状体神经元的选择性破坏取决于一系列独特的事件（通过多巴胺转运体转运到神经末梢，通过电动势定位在内线粒体膜中，以及抑制线粒体电子传递链的复合体I），幸运的是，许多物质不太可能出现这种情况。另一个有充分记录的代谢生物活化序列的例子涉及剧毒的吡咯里西啶生物碱（102）。这些化合物经过细胞色素P450催化的α-碳氧化，将母体生物碱中存在的3-吡咯啉基部分转化为含吡咯基的代谢物（105）。不稳定官能团的存在导致105自发转化为反应性亲电产物（106和108），这些产物与生物大分子上的亲核试剂发生迈克尔加成反应，导致各种毒性后果。对于可能由低水平、长期接触效力较低的毒素介导的神经退行性过程的潜在贡献，目前还不太明确。潜在的神经毒素前体的例子是内源性形成的四氢异喹啉（如40 - 50）和四氢-β-咔啉（如54），它们可能在脑内生物转化为神经毒性异喹啉鎓（如51）和β-咔啉鎓（如52）物质。对于4-哌啶醇（与四氢吡啶处于相同氧化态的化合物）也可以提出类似的观点，它们可能通过亚胺中间体代谢为氨基烯醇，氨基烯醇会自发转化为二氢吡啶鎓物质，进而转化为吡啶鎓代谢物（67→68→69→70→71，方案10）。这种反应序列在帕金森病诱导的抗精神病药物氟哌啶醇（72）中已有充分记录，它在人类、狒狒和啮齿动物体内代谢为吡啶鎓物质HPP⁺（75），这是一种线粒体呼吸的强效抑制剂。最后，认识到完全还原的氮杂环如（S）-尼古丁（61）和苯环己哌啶（82）的α-碳氧化生成与蛋白质形成共价加合物的化学反应性代谢物，包括负责其形成的酶，在试图解释长期滥用这些强效药物的影响时，可能具有毒理学重要性。
