Rotenone, Deguelin, Their Metabolites, and the Rat Model of Parkinson's Disease
详细信息 查看全文
- 作者：Pierluigi Caboni ; Todd B. Sherer ; Nanjing Zhang ; Georgia Taylor ; Hye Me Na ; J. Timothy Greenamyre ; and John E. Casida
- 刊名：Chemical Research in Toxicology
- 出版年：2004
- 出版时间：November 2004
- 年：2004
- 卷：17
- 期：11
- 页码：1540 - 1548
- 全文大小：243K
- 年卷期：v.17,no.11(November 2004)
- ISSN：1520-5010
文摘
Rotenone and deguelin are the major active ingredients and principal components of cubéresin from Lonchocarpus utilis used as a botanical insecticide and piscicide. They are alsopotent complex I (NADH:ubiquinone oxidoreductase) inhibitors. Rotenone was known earlier,and deguelin is shown here to induce a Parkinson's disease (PD)-like syndrome aftersubcutaneous treatment of rats by osmotic minipump. Rotenone at 3 mg/kg/day or deguelin at6 but not 3 mg/kg/day induces degeneration of the nigrostriatal dopaminergic pathway, asshown 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 0.4-1.3ppm but not with the much smaller brain level of 12a
le">-hydroxyrotenoids or other metabolitesanalyzed by HPLC and LC/MS. We previously established that the hydroxylated metabolitesand derivatives of rotenone and deguelin are all less active (i.e., detoxified) as complex Iinhibitors relative to the parent rotenoids. The PD-like syndrome induced in rats by rotenoneand deguelin is therefore due to the parent compounds rather than metabolites. Deguelin isabout half as active as rotenone in inducing the PD-like syndrome in rats and in acute ip LD50in mice. Rotenone and deguelin are metabolized by human recombinant 3A4 and 2C19 butnot five other P450 enzymes. 2C19 is more selective than 3A4 in forming the 12ale">-hydroxyrotenoids. Identified sites of metabolic attack individually or in combination are asfollows: 12ale"> hydroxylation and 2-O-demethylation of both compounds, oxidation of therotenone isopropenyl substituent to mono and diol derivatives, and probable oxidation of thedeguelin dimethylchromene double bond. These toxicological features must be considered inusing rotenone, deguelin, and their analogues as pesticides, candidate radioimaging and cancerchemopreventive agents, and models of PD.
le">-hydroxyrotenoids or other metabolitesanalyzed by HPLC and LC/MS. We previously established that the hydroxylated metabolitesand derivatives of rotenone and deguelin are all less active (i.e., detoxified) as complex Iinhibitors relative to the parent rotenoids. The PD-like syndrome induced in rats by rotenoneand deguelin is therefore due to the parent compounds rather than metabolites. Deguelin isabout half as active as rotenone in inducing the PD-like syndrome in rats and in acute ip LD50in mice. Rotenone and deguelin are metabolized by human recombinant 3A4 and 2C19 butnot five other P450 enzymes. 2C19 is more selective than 3A4 in forming the 12ale">-hydroxyrotenoids. Identified sites of metabolic attack individually or in combination are asfollows: 12ale"> hydroxylation and 2-O-demethylation of both compounds, oxidation of therotenone isopropenyl substituent to mono and diol derivatives, and probable oxidation of thedeguelin dimethylchromene double bond. These toxicological features must be considered inusing rotenone, deguelin, and their analogues as pesticides, candidate radioimaging and cancerchemopreventive agents, and models of PD.