Leiphon Laura J, Picklo Matthew J
Department of Pharmacology, Physiology, and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203, USA.
Neurotoxicology. 2007 Jan;28(1):143-9. doi: 10.1016/j.neuro.2006.08.008. Epub 2006 Sep 1.
Among the several converging factors leading to Parkinson's disease, epidemiological studies indicate a correlation between Parkinson's disease (PD) with living in a rural area and/or exposure to agricultural pesticides. In this present study, we examined the potential of multiple agricultural pesticides for their ability to inhibit the function of whole, respiring rat brain mitochondria using the oxidation of the neurotoxic lipid-aldehyde trans-4-hydroxy-2-nonenal (HNE) as a biomarker for mitochondrial aldehyde dehydrogenase (ALDH) activity in situ. We chose an arbitrary cutoff concentration of 10 microM of each pesticide. Our data demonstrate that only four of the eighteen compounds tested inhibited oxidation of HNE to trans-4-hydroxy-2-nonenoic acid (HNEAcid). These compounds included rotenone, maneb, mancozeb, and benomyl. Surprisingly, maneb, mancozeb, and benomyl did not inhibit mitochondrial respiration but inhibited the activity of purified rat ALDH2 and rat ALDH5A, enzymes found in brain mitochondria that oxidize HNE and aldehydes derived from neurotransmitters. Our data demonstrate that mitochondrial ALDHs are sensitive targets of pesticide inactivation and that pesticides such as maneb and benomyl can decrease the detoxification of lipid peroxidation derived aldehydes such as HNE and, likely, aldehydes derived from neurotransmitters.
在导致帕金森病的多种共同作用因素中，流行病学研究表明帕金森病（PD）与生活在农村地区和/或接触农用杀虫剂之间存在关联。在本研究中，我们以神经毒性脂质醛反式-4-羟基-2-壬烯醛（HNE）的氧化作为原位线粒体醛脱氢酶（ALDH）活性的生物标志物，研究了多种农用杀虫剂抑制完整的、进行呼吸作用的大鼠脑线粒体功能的潜力。我们为每种杀虫剂任意选择了10微摩尔的截止浓度。我们的数据表明，在所测试的18种化合物中，只有4种抑制了HNE氧化为反式-4-羟基-2-壬烯酸（HNE酸）。这些化合物包括鱼藤酮、代森锰、代森锰锌和苯菌灵。令人惊讶的是，代森锰、代森锰锌和苯菌灵并不抑制线粒体呼吸，但抑制纯化的大鼠ALDH2和大鼠ALDH5A的活性，这两种酶存在于脑线粒体中，可氧化HNE和神经递质衍生的醛。我们的数据表明，线粒体ALDH是农药失活的敏感靶点，代森锰和苯菌灵等农药可降低脂质过氧化衍生醛（如HNE）以及可能的神经递质衍生醛的解毒作用。
