Buckpitt A R, Warren D L
J Pharmacol Exp Ther. 1983 Apr;225(1):8-16.
Previous studies have shown that cytochrome P-450-mediated metabolism of naphthalene results in dose-dependent bronchiolar necrosis in mice and in the formation of reactive metabolites which deplete reduced glutathione and become bound covalently to tissue macromolecules. The finding that pulmonary glutathione levels were nearly totally depleted after large doses of naphthalene suggested that hepatic formation of reactive metabolites may contribute substantially to glutathione depletion and covalent binding in extrahepatic tissues. This possibility has been supported by several new lines of evidence: 1) similar levels of covalent binding were observed in lung, liver and kidney in vivo, yet the rate of kidney microsomal metabolic activation of naphthalene was much lower than in liver or lung; 2) phenobarbital pretreatment markedly increased in vivo covalent binding in lung, liver and kidney and increased hepatic but decreased pulmonary microsomal covalent binding; 3) 3-methylcholanthrene pretreatment resulted in slightly increased levels of covalent binding in lung, liver and kidney yet decreased pulmonary microsomal covalent binding; 4) administration of p-xylene, at doses which selectively decreased pulmonary microsomal metabolism of biphenyl (4-hydroxylation) and naphthalene (to reactive metabolites), decreased in vivo covalent binding in liver and kidney to the same extent as lung after [14C]naphthalene; and 5) pretreatment with buthionine sulfoximine preferentially depleted hepatic and renal but not pulmonary glutathione levels and markedly increased covalent binding in all three tissues. The severity of naphthalene-induced bronchiolar damage was unaffected by pretreatment with phenobarbital, 3-methylcholanthrene or p-xylene but was increased by prior administration of buthionine sulfoximine. These studies suggest that a portion of the reactive metabolites which deplete glutathione and bind covalently in extrahepatic tissues originate in the liver. Whether these circulating metabolites play a role in naphthalene-induced pulmonary bronchiolar damage is not clear.
先前的研究表明，细胞色素P - 450介导的萘代谢会导致小鼠出现剂量依赖性细支气管坏死，并形成活性代谢产物，这些产物会消耗还原型谷胱甘肽，并与组织大分子共价结合。大剂量萘给药后肺组织中谷胱甘肽水平几乎完全耗尽这一发现表明，活性代谢产物在肝脏中的形成可能在很大程度上导致肝外组织中谷胱甘肽的耗尽和共价结合。这一可能性得到了几条新证据的支持：1）在体内肺、肝和肾中观察到相似水平的共价结合，但肾微粒体对萘的代谢活化率远低于肝或肺；2）苯巴比妥预处理显著增加了体内肺、肝和肾中的共价结合，并增加了肝脏但降低了肺微粒体的共价结合；3）3 - 甲基胆蒽预处理导致肺、肝和肾中共价结合水平略有增加，但降低了肺微粒体的共价结合；4）给予对二甲苯，其剂量能选择性降低肺微粒体对联苯（4 - 羟基化）和萘（生成活性代谢产物）的代谢，在给予[14C]萘后，肝和肾中的体内共价结合减少程度与肺相同；5）用丁硫氨酸亚砜胺预处理优先耗尽肝脏和肾脏而非肺组织中的谷胱甘肽水平，并显著增加所有三个组织中的共价结合。萘诱导的细支气管损伤的严重程度不受苯巴比妥、3 - 甲基胆蒽或对二甲苯预处理的影响，但丁硫氨酸亚砜胺预先给药会使其加重。这些研究表明，一部分在肝外组织中消耗谷胱甘肽并共价结合的活性代谢产物起源于肝脏。这些循环代谢产物是否在萘诱导的肺细支气管损伤中起作用尚不清楚。
