Han Q P, Dryhurst G
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, USA.
J Med Chem. 1996 Mar 29;39(7):1494-508. doi: 10.1021/jm9504870.
Recent evidence suggests that intraneuronal metabolism of ethanol by catalase/H2O2 and an ethanol-inducible form of cytochrome P450 together generate acetaldehyde and oxygen radicals including the hydroxyl radical (HO.). Within the cytoplasm of serotonergic neurons, these metabolic processes would thus provide acetaldehyde, which would react with unbound 5-hydroxytryptamine (5-HT) to give 1-methyl-6-hydroxy-1,2,3,4-tetrahydro-beta-carboline (1), known to be formed at elevated levels in the brain following ethanol drinking, and HO. necessary to oxidize this alkaloid. In this study, it is demonstrated that the HO.-mediated oxidation of 1 at physiological pH yields 1-methyl-1,2,3,4-tetrahydro-beta-carboline-5,6-dione (8) that reacts avidly with free glutathione (GSH), a significant constituent of axons and nerve terminals, to give diastereomers of 8-S-glutathionyl-1-methyl-1,2,3,4-tetrahydro-beta-carboline-5,6-dione (9A and 9B). In the presence of free GSH, ascorbic acid, other intraneuronal antioxidants/reductants, and molecular oxygen diastereomers, 9A/9B redox cycle in reactions that generate H2O2 and, via trace transition metal ion catalyzed decomposition of the latter compound, HO.. Further reactions of 9A/9B with GSH and/or HO. generate several additional glutathionyl conjugates that also redox cycle in the presence of intraneuronal reductants and molecular oxygen forming H2O2 and HO.. Thus, intraneuronal formation of 1 and HO. as a consequence of ethanol drinking and resultant endogenous synthesis of 8,9A, and 9B would, based on these in vitro chemical studies, be expected to generate elevated fluxes of H2O2 and HO. leading to oxidative damage to serotonergic axons and nerve terminals and the irreversible loss of GSH, both of which occur in the brain as a consequence of ethanol drinking. Furthermore, deficiencies of 5-HT and loss of certain serotonergic pathways in the brain have been linked to the preference for and addiction to ethanol.
最近的证据表明，过氧化氢酶/H₂O₂和乙醇诱导型细胞色素P450共同作用使乙醇在神经元内代谢，生成乙醛和包括羟基自由基（HO·）在内的氧自由基。在5-羟色胺能神经元的细胞质中，这些代谢过程会产生乙醛，乙醛会与游离的5-羟色胺（5-HT）反应生成1-甲基-6-羟基-1,2,3,4-四氢-β-咔啉（1），已知在饮酒后大脑中该物质水平会升高，同时还会产生氧化这种生物碱所需的HO·。在本研究中，已证明在生理pH值下，HO·介导的1的氧化反应生成1-甲基-1,2,3,4-四氢-β-咔啉-5,6-二酮（8），它会与游离谷胱甘肽（GSH）（轴突和神经末梢的一种重要成分）迅速反应，生成8-S-谷胱甘肽基-1-甲基-1,2,3,4-四氢-β-咔啉-5,6-二酮（9A和9B）的非对映异构体。在游离GSH、抗坏血酸、其他神经元内抗氧化剂/还原剂以及分子氧非对映异构体存在的情况下，9A/9B在反应中发生氧化还原循环，生成H₂O₂，并通过痕量过渡金属离子催化后者化合物的分解生成HO·。9A/9B与GSH和/或HO·的进一步反应会生成几种额外的谷胱甘肽基共轭物，它们在神经元内还原剂和分子氧存在的情况下也会发生氧化还原循环，生成H₂O₂和HO·。因此，基于这些体外化学研究，饮酒导致神经元内生成1和HO·以及由此产生的8、9A和9B的内源性合成，预计会导致H₂O₂和HO·通量增加，从而对5-羟色胺能轴突和神经末梢造成氧化损伤，并导致GSH不可逆地损失，这两种情况在饮酒后的大脑中都会发生。此外，大脑中5-羟色胺的缺乏和某些5-羟色胺能通路的丧失与对乙醇的偏好和成瘾有关。
