J Biol Chem:抵消酒精、烟草和某些食物中有害健康化合物的新药线索

2019-06-27 佚名 生物通

30多年前,科学家们发现,在合成类阿片MPTP中发现的一种化学物质会导致帕金森病发作。宾夕法尼亚大学的科学家领导的一项新研究,研究人员发现,人体内的一种酶可将烟草和某些食物中的生物碱转化为MPTP样化合物,从而引发小鼠大脑神经退化。

30多年前,科学家们发现,在合成类阿片MPTP中发现的一种化学物质会导致帕金森病发作。宾夕法尼亚大学的科学家领导的一项新研究,研究人员发现,人体内的一种酶可将烟草和某些食物中的生物碱转化为MPTP样化合物,从而引发小鼠大脑神经退化。



在Narayan Avadhani和Mrittika Chattopadhayay的领导下,研究人员认为这种酶,线粒体CYP2D6,可能是治疗帕金森的新靶点。

“在过去的二三十年里,研究人员试图抑制MPTP代谢过程,并且取得了不同程度的成功,”Avadhani说。“我们认为线粒体CYP2D6是更直接的药物靶点,它可能在治疗特发性帕金森病方面效果更好。”

这项研究发表在《Journal of Biological Chemistry》上。有关帕金森病的发病机制,其中一个特定的病因无法确定,即占比很高的化学诱发疾病。

先前的研究表明,MPTP和类似的有毒化合物在啮齿动物和灵长类动物中会诱发帕金森。科学家们理解,这种作用机制涉及化合物被氧化形成为一种有毒的代谢物MPP+。罪魁祸首被认定为是存在于神经胶质细胞中的一种单胺氧化酶B(MAO-B)。在这种机制概念中,人们认为MPP+通过多巴胺转运蛋白转移至多巴胺神经元。然而,实际上,帕金森的特征之一反而是大脑中多巴胺水平异常低。

因此,有些研究人员试图假定,在这个途径中有两个参与者,MAO-B和多巴胺转运蛋白,但同时靶向这两个蛋白来阻止帕金森的影响的成功率参差不齐。

宾夕法尼亚大学领导的这项新研究指出了一个完全独立的机制。

在早期的研究中,Avadhani和同事们证明,定位于线粒体的一种酶CYP2D6在MPTP代谢为MPP+中发挥作用。新调查中,他们更仔细地观察了类似MPTP的毒素——β-咔啉和异喹啉——人体从烟草、酒精以及某些食物中获得进而代谢产生。

他们发现,并非MAO-B,而是线粒体CYP2D6激活了多巴胺生产神经元(而非胶质细胞)内的β-咔啉和异喹啉。在小鼠模型中,该激活途径会导致神经元损伤和氧化应激,症状类似帕金森症。

“众所周知,CYP2D6在影响许多药物的活性方面发挥了作用,”Avadhani

在一次靶向该途径的尝试中,研究人员发现缺乏CYP2D6的小鼠没有表现出严重症状。此外,一种CYP2D6抑制剂可以防止神经元损伤。

“CYP2D6抑制剂ajmalicine是利血平生物碱家族的一员,存在于一种萝芙木植物(Rauwolfia serpentine)中,在印度,它被用来治疗妄想症和精神分裂症等精神疾病,”Avadhani说。“这种化合物的线粒体靶向性可能对治疗帕金森病有效,这是我们未来的研究目标之一。”

原始出处:Chattopadhyay M1, Roy Chowdhury A2, Feng T3, et al. Mitochondria-targeted cytochrome P450 CYP2D6 is involved in monomethylamine-induced neuronal damage in mouse models. J Biol Chem. 2019 May 20. 

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    2019-12-22 sunylz
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likeNumber=3, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfNLvzZhgPxRkia1DP5MpwEgtXo1XhXA11xD6MWKxunAZFXKSNic0fWHUQx83oNHPlRMxxIctM83QKeCLkJpMibibiaC/0, createdBy=7e581734408, createdName=深海的鱼, createdTime=Thu Jun 27 06:45:55 CST 2019, time=2019-06-27, status=1, ipAttribution=)]
    2019-07-05 百草

    666

    0

  5. 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topicName=null, topicId=null, topicList=[TopicDto(id=67111, encryptionId=53036e11185, topicName=烟草)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6a8d381, createdName=mnda, createdTime=Fri Jun 28 15:54:00 CST 2019, time=2019-06-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1416863, encodeId=bd09141686366, content=<a href='/topic/show?id=27c710101804' target=_blank style='color:#2F92EE;'>#食物#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=101018, encryptionId=27c710101804, topicName=食物)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=e3a33221853, createdName=yhy100201, createdTime=Fri Jun 28 15:54:00 CST 2019, time=2019-06-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=368438, encodeId=d3ec36843803, content=666, beContent=null, objectType=article, channel=null, level=null, likeNumber=79, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cdnapi.center.medsci.cn/medsci/head/2019/01/04/2540fb84decb81d47a7f2868070e6cbd.jpg, createdBy=ed3f2205793, createdName=百草, createdTime=Thu Jun 27 07:10:56 CST 2019, time=2019-06-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=368435, encodeId=71e836843510, content=666, beContent=null, objectType=article, channel=null, level=null, likeNumber=82, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cdnapi.center.medsci.cn/medsci/head/2019/01/04/2540fb84decb81d47a7f2868070e6cbd.jpg, createdBy=ed3f2205793, createdName=百草, createdTime=Thu Jun 27 07:09:13 CST 2019, time=2019-06-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=368432, encodeId=653636843299, content=学习学习学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=3, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfNLvzZhgPxRkia1DP5MpwEgtXo1XhXA11xD6MWKxunAZFXKSNic0fWHUQx83oNHPlRMxxIctM83QKeCLkJpMibibiaC/0, createdBy=7e581734408, createdName=深海的鱼, createdTime=Thu Jun 27 06:45:55 CST 2019, time=2019-06-27, status=1, ipAttribution=)]
    2019-07-01 百草

    666

    0

  6. 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topicName=null, topicId=null, topicList=[TopicDto(id=67111, encryptionId=53036e11185, topicName=烟草)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6a8d381, createdName=mnda, createdTime=Fri Jun 28 15:54:00 CST 2019, time=2019-06-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1416863, encodeId=bd09141686366, content=<a href='/topic/show?id=27c710101804' target=_blank style='color:#2F92EE;'>#食物#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=101018, encryptionId=27c710101804, topicName=食物)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=e3a33221853, createdName=yhy100201, createdTime=Fri Jun 28 15:54:00 CST 2019, time=2019-06-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=368438, encodeId=d3ec36843803, content=666, beContent=null, objectType=article, channel=null, level=null, likeNumber=79, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cdnapi.center.medsci.cn/medsci/head/2019/01/04/2540fb84decb81d47a7f2868070e6cbd.jpg, createdBy=ed3f2205793, createdName=百草, createdTime=Thu Jun 27 07:10:56 CST 2019, time=2019-06-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=368435, encodeId=71e836843510, content=666, beContent=null, objectType=article, channel=null, level=null, likeNumber=82, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cdnapi.center.medsci.cn/medsci/head/2019/01/04/2540fb84decb81d47a7f2868070e6cbd.jpg, createdBy=ed3f2205793, createdName=百草, createdTime=Thu Jun 27 07:09:13 CST 2019, time=2019-06-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=368432, encodeId=653636843299, content=学习学习学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=3, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfNLvzZhgPxRkia1DP5MpwEgtXo1XhXA11xD6MWKxunAZFXKSNic0fWHUQx83oNHPlRMxxIctM83QKeCLkJpMibibiaC/0, createdBy=7e581734408, createdName=深海的鱼, createdTime=Thu Jun 27 06:45:55 CST 2019, time=2019-06-27, status=1, ipAttribution=)]
    2019-06-28 mnda
  7. 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likeNumber=3, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfNLvzZhgPxRkia1DP5MpwEgtXo1XhXA11xD6MWKxunAZFXKSNic0fWHUQx83oNHPlRMxxIctM83QKeCLkJpMibibiaC/0, createdBy=7e581734408, createdName=深海的鱼, createdTime=Thu Jun 27 06:45:55 CST 2019, time=2019-06-27, status=1, ipAttribution=)]
    2019-06-28 yhy100201
  8. 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likeNumber=3, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfNLvzZhgPxRkia1DP5MpwEgtXo1XhXA11xD6MWKxunAZFXKSNic0fWHUQx83oNHPlRMxxIctM83QKeCLkJpMibibiaC/0, createdBy=7e581734408, createdName=深海的鱼, createdTime=Thu Jun 27 06:45:55 CST 2019, time=2019-06-27, status=1, ipAttribution=)]
    2019-06-27 百草

    666

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  9. 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    2019-06-27 百草

    666

    0

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    2019-06-27 深海的鱼

    学习学习学习

    0

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