Caboni Pierluigi, Sherer Todd B, Zhang Nanjing, Taylor Georgia, Na Hye Me, Greenamyre J Timothy, Casida John E
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, California 94720-3112, USA.
Chem Res Toxicol. 2004 Nov;17(11):1540-8. doi: 10.1021/tx049867r.
Rotenone and deguelin are the major active ingredients and principal components of cuberesin 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 dimethylchromene 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.
鱼藤酮和脱氢鱼藤素是毛鱼藤根树脂的主要活性成分和主要组分，毛鱼藤根树脂被用作植物杀虫剂和鱼毒剂。它们也是强效的复合物I（NADH：泛醌氧化还原酶）抑制剂。鱼藤酮早为人知，本文显示，通过渗透微型泵皮下给药处理大鼠后，脱氢鱼藤素会诱发帕金森病（PD）样综合征。3mg/kg/天的鱼藤酮或6mg/kg/天而非3mg/kg/天的脱氢鱼藤素会诱发黑质纹状体多巴胺能通路变性，这在5或6天的处理后通过酪氨酸羟化酶免疫反应性降低得以体现。神经病理损伤与母体鱼藤酮类物质在脑中的含量水平为0.4 - 1.3ppm有关，但与通过高效液相色谱法（HPLC）和液相色谱 - 质谱联用（LC/MS）分析的含量水平低得多的12αβ - 羟基鱼藤酮类物质或其他代谢物无关。我们之前确定，相对于母体鱼藤酮类物质，鱼藤酮和脱氢鱼藤素的羟基化代谢物和衍生物作为复合物I抑制剂的活性都较低（即解毒）。因此，鱼藤酮和脱氢鱼藤素在大鼠中诱发的PD样综合征是由母体化合物而非代谢物导致的。在诱发大鼠PD样综合征以及小鼠急性腹腔注射半数致死剂量（LD50）方面，脱氢鱼藤素的活性约为鱼藤酮的一半。鱼藤酮和脱氢鱼藤素可被人重组3A4和2C19代谢，但不能被其他五种细胞色素P450酶代谢。在形成12αβ - 羟基鱼藤酮类物质方面，2C19比3A4更具选择性。已确定的单独或联合的代谢攻击位点如下：两种化合物的12αβ羟基化和2 - O - 去甲基化、鱼藤酮异丙烯基取代基氧化为单醇和二醇衍生物，以及脱氢鱼藤素二甲基色烯双键可能的氧化。在将鱼藤酮、脱氢鱼藤素及其类似物用作杀虫剂、候选放射性成像剂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。
