RELATIONSHIP OF FREE RADICALS TO HALOCARBON-INDUCED TOXICITY IN THE LIVER

自由基与卤代烃引起的肝脏毒性的关系

• 批准号: 3918692
• 负责人: R P MASON
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3918692
• 关键词: anesthetics; carbon dioxide; cell membrane; cytochrome P450; drug adverse effect; electron spin resonance spectroscopy; free radicals; hepatotoxin; ion transport; laboratory rat; lactate dehydrogenases; metyrapone; molecular biology; phenobarbital

CC14 has been shown previously to be metabolized to the trichloromethyl radical (.CC13) and to a novel oxygen-containing carbon dioxide anion radical (.C02-) in the perfused rat liver. These free radicals were detected by electron spin resonance using the spin-trapping technique. The .C02- radical adduct also was observed in urine following the intragastric administration of CC14 or CBrC13 and spin trap. Detection of the .C02- adduct in the effluent perfusate was decreased 3-4 fold by DIDS (0.2 mM), an inhibitor of the plasma membrane anion transport system. The rate of formation of .CO2- radical adduct was decreased 2-3 fold following inhibition of cytochrome P-450-dependent mono-oxygenases by metyrapone (0.5 mM) and was increased about two-fold by induction of cytochrome P-450 by phenobarbital pretreatment. Toxicity of halocarbons in the perfused liver was assessed by measuring the release of lactate dehydrogenase (LDH) into the effluent perfusate in livers from phenobarbital-treated rats under conditions identical to those employed to detect radical adducts (i.e., during the infusion of CC14 or CBrC13 into livers perfused with either nitrogen- or oxygen-saturated perfusate). Metabolism of halocarbons to .C02- radical adduct was 6-8 fold faster during perfusion with nitrogen-saturated rather than with oxygen-saturated perfusate. Concomitantly, liver damage detected from LDH release occurred much sooner during halocarbon infusion in the presence of nitrogen-saturated perfusate. A good correlation (r= -0.80) between the rate of formation of PBN/.C02- and the time to onset of LDH release following halocarbon infusion was observed. Therefore, it is concluded that PBN/.C02- is a useful marker for oxygen-containing free radical intermediates which may be causally related to halocarbon-induced hepatotoxicity. Recently, the .CC13 and .C02-radical adducts also have been detected in the bile from anesthetized rats.

CC14先前已被证明已代谢为 三氯甲基自由基（.cc13）和新型含氧 灌注大鼠肝脏中的二氧化碳阴离子（.c02-）。 通过使用电子自旋共振检测到这些自由基 旋转诱捕技术。 .c02-自由基加合物也是 在胃内给药CC14之后，在尿液中观察到 或CBRC13和自旋陷阱。 检测.c02加合物 涂料（0.2毫米）减少了流出的灌注液3-4倍， 质膜阴离子传输系统的抑制剂。 费率 .co2-自由基加合物的形成2-3倍 抑制细胞色素P-450依赖性单氧酶 通过metyrapone（0.5毫米），增加了约2倍 通过苯巴比妥预处理诱导细胞色素P-450。 通过 测量乳酸脱氢酶（LDH）释放到 从苯巴比妥治疗的大鼠肝脏中的流出灌注液 条件与检测自由基加合物的疾病相同 （即，在将CC14或CBRC13输注到肝脏中 与氮或氧饱和灌注液一起使用）。 代谢 在.c02-自由基加合物中的卤代碳的速度速度快6-8倍 用氮饱和而不是用氧饱和的灌注 灌注液。 同时，从LDH释放中检测到的肝损害 在盐水输注期间，发生在 氮饱和灌注液。 良好的相关性（r = -0.80） 在PBN/.C02-的形成率与发作时间之间 观察到盐输注后LDH释放的释放。 因此，可以得出结论，PBN/.C02-是有用的标记 含氧的自由基中间体可能是因果 与盐碳诱导的肝毒性有关。 最近，.cc13 和.c02-Radical加合物也在胆汁中检测到 麻醉大鼠。