Murphy Tonya C, Amarnath Venkataraman, Gibson K Michael, Picklo Matthew J
Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58203, USA.
J Neurochem. 2003 Jul;86(2):298-305. doi: 10.1046/j.1471-4159.2003.01839.x.
Elevated levels of 4-hydroxy-trans-2-nonenal (HNE) are implicated in the pathogenesis of numerous neurodegenerative disorders. Although well-characterized in the periphery, the mechanisms of detoxification of HNE in the CNS are unclear. HNE is oxidized to a non-toxic metabolite in the rat cerebral cortex by mitochondrial aldehyde dehydrogenases (ALDHs). Two possible ALDH enzymes which might oxidize HNE in CNS mitochondria are ALDH2 and succinic semialdehyde dehydrogenase (SSADH/ALDH5A). It was previously established that hepatic ALDH2 can oxidize HNE. In this work, we tested the hypothesis that SSADH oxidizes HNE. SSADH is critical in the detoxification of the GABA metabolite, succinic semialdehyde (SSA). Recombinant rat SSADH oxidized HNE and other alpha,beta-unsaturated aldehydes. Inhibition and competition studies in rat brain mitochondria showed that SSADH was the predominant oxidizing enzyme for HNE but only contributed a portion of the total oxidizing activity in liver mitochondria. In vivo administration of diethyldithiocarbamate (DEDC) effectively inhibited (86%) ALDH2 activity but not HNE oxidation in liver mitochondria. The data suggest that a relationship between the detoxification of SSA and the neurotoxic aldehyde HNE exists in the CNS. Furthermore, these studies show that multiple hepatic aldehyde dehydrogenases are able to oxidize HNE.
4-羟基反式-2-壬烯醛（HNE）水平升高与多种神经退行性疾病的发病机制有关。尽管HNE在外周组织中的特性已得到充分研究，但其在中枢神经系统（CNS）中的解毒机制尚不清楚。在大鼠大脑皮层中，HNE可被线粒体醛脱氢酶（ALDHs）氧化为无毒代谢产物。两种可能在CNS线粒体中氧化HNE的ALDH酶是ALDH2和琥珀酸半醛脱氢酶（SSADH/ALDH5A）。此前已证实肝脏中的ALDH2可氧化HNE。在本研究中，我们检验了SSADH氧化HNE的假说。SSADH在γ-氨基丁酸（GABA）代谢产物琥珀酸半醛（SSA）的解毒过程中起关键作用。重组大鼠SSADH可氧化HNE及其他α,β-不饱和醛。对大鼠脑线粒体进行的抑制和竞争研究表明，SSADH是HNE的主要氧化酶，但在肝线粒体的总氧化活性中仅占一部分。体内给予二乙基二硫代氨基甲酸盐（DEDC）可有效抑制（86%）肝线粒体中的ALDH2活性，但不影响HNE的氧化。这些数据表明，CNS中存在SSA解毒与神经毒性醛HNE之间的关联。此外，这些研究表明多种肝脏醛脱氢酶能够氧化HNE。
