Niknahad Hossein, Shuhendler Adam, Galati Giuseppe, Siraki Arno G, Easson Elaine, Poon Raymond, O'Brien Peter J
Faculty of Pharmacy, Department of Pharmacology and Toxicology, Shiraz University of Medical Sciences, Shiraz, 71345, Fars, Iran.
Chem Biol Interact. 2003 Feb 1;143-144:119-28. doi: 10.1016/s0009-2797(02)00195-3.
The molecular cytotoxic mechanisms of dietary benzaldehydes towards hepatocytes and its modulation by metabolizing enzymes were compared. Salicylaldehyde was found to be the most cytotoxic followed by cinnamaldehyde and both rapidly depleted some glutathione before an inhibition of respiration occurred, which preceded cell lysis. Reactive oxygen species were formed, but lipid peroxidation was induced with cinnamaldehyde, but not salicylaldehyde. Glutathione depleted hepatocytes were more susceptible to cytotoxicity. Mitochondrial toxicity and cytotoxicity were prevented by glycolytic substrates (e.g. fructose), citric acid cycle substrates (e.g. glutamine) or cyclosporin, the mitochondrial permeability transition inhibitor. Inhibition of mitochondrial ALDH with chloral hydrate, crotonaldehyde or citral or decreasing mitochondrial NAD+ with rotenone increased cinnamaldehyde induced cytotoxicity with a much smaller effect on salicylaldehyde induced cytotoxicity. Cyanamide was the most effective ALDH inhibitor for increasing cinnamaldehyde induced cytotoxicity, presumably because cyanamide also inhibits microsomal ALDH. Although cinnamaldehyde was a better substrate than salicylaldehyde for ADH1, cytosolic NADH generators (e.g. xylitol) prevented salicylaldehyde and cinnamaldehyde cytotoxicity similarly. This could be explained as salicylaldehyde was not a substrate for the ALDHs and would then be more dependent on ADH for detoxification.
比较了膳食苯甲醛对肝细胞的分子细胞毒性机制及其受代谢酶的调节作用。发现水杨醛的细胞毒性最大，其次是肉桂醛，两者在抑制呼吸发生之前都会迅速消耗一些谷胱甘肽，而呼吸抑制先于细胞裂解。会形成活性氧，但肉桂醛会诱导脂质过氧化，而水杨醛则不会。谷胱甘肽耗尽的肝细胞对细胞毒性更敏感。糖酵解底物（如果糖）、柠檬酸循环底物（如谷氨酰胺）或线粒体通透性转换抑制剂环孢素可预防线粒体毒性和细胞毒性。用水合氯醛、巴豆醛或柠檬醛抑制线粒体醛脱氢酶（ALDH），或用鱼藤酮降低线粒体NAD⁺，会增加肉桂醛诱导的细胞毒性，而对水杨醛诱导的细胞毒性影响较小。氰胺是增加肉桂醛诱导细胞毒性最有效的ALDH抑制剂，可能是因为氰胺也抑制微粒体ALDH。尽管肉桂醛比水杨醛是更好的乙醇脱氢酶1（ADH1）底物，但胞质NADH生成剂（如木糖醇）对水杨醛和肉桂醛细胞毒性的预防作用相似。这可以解释为水杨醛不是ALDHs的底物，因此在解毒方面更依赖ADH。
