Rotenone, deguelin, their metabolites, and the rat model of Parkinson's disease
Rotenone, deguelin, their metabolites, and the rat model of Parkinson's disease
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DOI：
10.1021/tx049867r
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发表时间：
2004-11-01
影响因子：
4.1
通讯作者：
Casida, JE
中科院分区：
文献类型：
--
作者：
Caboni, P;Sherer, TB;Casida, JE
鱼藤酮和鱼藤素是刺果香豆树脂的主要活性成分，是植物源杀虫剂和杀鱼剂。它们也是有效的复合物I（NADH：泛醌氧化还原酶）抑制剂。鱼藤酮是已知的较早，鱼藤素是在这里显示诱导帕金森氏病（PD）样综合征后，皮下治疗大鼠渗透微型泵。3 mg/kg/天的鱼藤酮或6 mg/kg/天但不是3 mg/kg/天的鱼藤素诱导黑质纹状体多巴胺能通路的变性，如处理5或6天后酪氨酸羟化酶免疫反应性降低所示。神经病。病变与0.4- 1.3ppm的母体类鱼藤素的脑水平有关，但与通过HPLC和LC/MS分析的12 β-羟基类鱼藤素或其它代谢物的小得多的脑水平无关。我们先前确定鱼藤酮和鱼藤素的羟基化代谢物和衍生物都活性较低（即，解毒）作为相对于母体类鱼藤素的复合物I抑制剂。因此，鱼藤酮和鱼藤素在大鼠中诱导的PD样综合征是由于母体化合物而不是代谢产物。鱼藤素在诱导大鼠PD样综合征和小鼠急性ip LD 50方面的活性约为鱼藤酮的一半。鱼藤酮和鱼藤素被人重组3A 4和2C 19代谢，但不被其他五种P450酶代谢。2C 19比3A 4在形成12 β-羟基类鱼藤素方面具有更高的选择性。已确定的代谢攻击位点单独或组合如下：12 abeta羟基化和2-O-去甲基化的两种化合物，氧化的鱼藤酮异丙烯基取代单和二醇衍生物，和可能的氧化鱼藤素dimethylehromene双键。在使用鱼藤酮、鱼藤素及其类似物作为杀虫剂、候选放射成像和癌症化学预防剂以及PD模型时，必须考虑这些毒理学特征。
Rotenone and deguelin are the major active ingredients and principal components of cube resin from Lonchocarpus utilis used as a botanical insecticide and piscicide. They are also potent complex I (NADH:ubiquinone oxidoreductase) inhibitors. Rotenone was known earlier, and deguelin is shown here to induce a Parkinson's disease (PD)-like syndrome after subcutaneous treatment of rats by osmotic minipump. Rotenone at 3 mg/kg/day or deguelin at 6 but not 3 mg/kg/day induces degeneration of the nigrostriatal dopaminergic pathway, as shown by reduced tyrosine hydroxylase immunoreactivity with treatments for 5 or 6 days. The neuropathological. lesions are associated with a brain level of parent rotenoid of 0.4-1.3 ppm but not with the much smaller brain level of 12abeta-hydroxyrotenoids or other metabolites analyzed by HPLC and LC/MS. We previously established that the hydroxylated metabolites and derivatives of rotenone and deguelin are all less active (i.e., detoxified) as complex I inhibitors relative to the parent rotenoids. The PD-like syndrome induced in rats by rotenone and deguelin is therefore due to the parent compounds rather than metabolites. Deguelin is about half as active as rotenone in inducing the PD-like syndrome in rats and in acute ip LD50 in mice. Rotenone and deguelin are metabolized by human recombinant 3A4 and 2C19 but not five other P450 enzymes. 2C19 is more selective than 3A4 in forming the 12abeta-hydroxyrotenoids. Identified sites of metabolic attack individually or in combination are as follows: 12abeta hydroxylation and 2-O-demethylation of both compounds, oxidation of the rotenone isopropenyl substituent to mono and diol derivatives, and probable oxidation of the deguelin dimethylehromene double bond. These toxicological features must be considered in using rotenone, deguelin, and their analogues as pesticides, candidate radioimaging and cancer chemopreventive agents, and models of PD.