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.

CC 14以前已被证明代谢为 三氯甲基自由基（.CC13），并涉及一种新的含氧 二氧化碳阴离子自由基（. CO2-）。 这些自由基通过电子自旋共振检测， 自旋捕获技术 CO2-自由基加合物也是 CC 14胃内给药后在尿液中观察到 或CBrC 13和自旋阱。 CO2-加合物的检测 DIDS（0.2 mM）使流出液灌注液减少3-4倍， 质膜阴离子转运系统的抑制剂。 率 CO2-自由基加合物的形成减少了2-3倍 在抑制细胞色素P-450依赖性单加氧酶后 通过甲吡酮（0.5 mM），并增加约2倍， 苯巴比妥预处理诱导细胞色素P-450。 卤烃在灌注肝脏中的毒性通过以下方法评估： 测量乳酸脱氢酶（LDH）释放到 苯巴比妥处理的大鼠肝脏中的流出液灌注 与检测自由基加合物所用的条件相同 (i.e.,在将CC 14或CBrC 13输注到灌注的肝脏中期间， 用氮或氧饱和的灌注液）。 代谢 卤化碳转化为CO2-自由基加合物的速度是其6-8倍。 氮饱和灌注而不是氧饱和灌注 灌注液 同时，从LDH释放检测到肝损伤 在存在卤化碳的情况下， 氮饱和灌注液。 良好的相关性（r= -0.80） PBN/CO2-的形成速率和至发作的时间之间的关系 观察到卤化碳输注后LDH释放的增加。 因此，可以得出结论，PBN/.C02-是一种有用的标记物， 含氧自由基中间体，其可能导致 与卤烃诱导的肝毒性有关。 近日，.CC13 和.C02-自由基加合物也已在胆汁中检测到， 麻醉大鼠。