IMPLICATION OF RIFAMPICIN-QUINONE IN IRREVERSIBLE BINDING OF RIFAMPICIN TO MACROMOLECULES
IMPLICATION OF RIFAMPICIN-QUINONE IN IRREVERSIBLE BINDING OF RIFAMPICIN TO MACROMOLECULES
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DOI：
10.3109/00498257609151608
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发表时间：
1976-01-01
期刊：
影响因子：
1.8
通讯作者：
REMMER, H
中科院分区：
文献类型：
--
作者：
BOLT, HM;REMMER, H
当[~3H]利福平与大鼠肝微粒体或大鼠肝匀浆孵育时，微量的蛋白质不可逆地结合到蛋白质上。这种作用不依赖于NAD、NADH、NADP或NADPH的存在。利福平在生理pH下自氧化。自氧化的产物，利福平-醌，如果与白蛋白孵育，与蛋白质的不可逆结合比母体化合物利福平强得多。利福平在自氧化为利福平-醌后，可能在非酶反应中不可逆地与蛋白质结合。如果与这些化合物孵育，利福平-醌也会不可逆地与核糖核酸和多L赖氨酸结合。这表明蛋白质或RNA的自由氨基参与了结合。大鼠注射[~3H]利福平(33 mg/kg)48小时后，29.2±-。4.1(SD)pmol不可逆地与1 mg肝RNA结合，15.8+-。8.1pmo1毫克肝蛋白和5.0.+-。脑组织中蛋白质含量为0.47pmol~1 mg。微粒体NADPH-细胞色素c还原酶能将利福平-醌还原为利福平。此反应的Km为10~(-4)M。用20 mg/kg利福平预先处理大鼠5天，可诱导NADPH-细胞色素C还原酶，相应地增加利福平-醌的还原。微粒体NADPH-细胞色素c还原酶可能通过还原为利福平来防止较高剂量的可能有毒的利福平-苯二酚的积累。
When [3H]rifampicin is incubated with rat liver microsomes or rat liver homogenate, minor amounts are bound irreversibly to protein. This effect does not depend on the presence of NAD, NADH, NADP or NADPH. Rifampicin is autoxidized at physiological pH. The product of autoxidation, rifampicin-quinone, if incubated with albumin, shows a much greater irreversible binding to the protein than the parent compound rifampicin. Rifampicin may bind irreversibly to proteins in a non-enzymic reaction after autoxidation to rifampicin-quinone. Rifampicin-quinone also binds irreversibly to RNA and poly-L-lysine, if incubated with these compounds. This suggests that free amino groups of protein or RNA are involved in the binding. Forty-eight hours after dosage of [3H]rifampicin (33 mg/kg) to rats, 29.2 .+-. 4.1 (SD) pmol are bound irreversibly to 1 mg liver RNA, 15.8 .+-. 8.1 pmol to 1 mg liver protein and 5.0 .+-. 0.47 pmol to 1 mg protein in brain tissue. Microsomal NADPH-cytochrome c reductase is able to reduce rifampicin-quinone to rifampicin. The KM of this reaction is 10-4 M. Induction of the NADPH-cytochrome c reductase by pre-treatment of rats with 20 mg/kg rifampicin over 5 days results in a corresponding increase of rifampicin-quinone reduction. Microsomal NADPH-cytochrome c reductase may prevent accumulation of higher amounts of possibly toxic rifampicin-quinone by reduction to rifampicin.