Abstract
Since evidence had been published that lysosomes are disrupted by a free radical-like agent produced during the oxidation of NADPH by liver microsomes, the nature of this free radical was investigated. The following data are presented. 1. The oxidation of NADPH by liver microsomes in the presence of ADP and Fe3+ produced a factor with properties of a free radical which caused the lysis of lysosomes. The addition of superoxide dismutase enhanced the lysis. 2. Lysis of lysosomes also was mediated by the oxidation of NADPH by a partially purified NADPH-cytochrome P450 reductase. 3. The oxidation of xanthine by xanthine oxidase in the presence of ADP and Fe3+ produced a radical capable of causing lysosomal lysis. Here again superoxide dismutase caused an enhancement of this lysis. 4. It was demonstrated that the superoxide free radical per se was not the agent causing lysis. Evidence is presented that the free radical causing the lysis of the lysosomes is the hydroxyl free radical (OH·). 5. During lysosomal lysis by the OH· radical, peroxidation of the lysosomal lipids was observed as assayed by the formation of malondialdehyde. 6. The mechanisms whereby superoxide and hydroxyl free radicals may be produced and interact with lysosomal membranes are discussed.
Highlights
Since evidence had been published that lysosomes are disrupted by a free radical-like agent produced during the oxidation of NADPH by liver microsomes, the nature of this free radical was investigated
Lysis of lysosomes was mediated by the oxidation of NADPH by a partially purified NADPH-cytochrome P460 reductase
More recently we reported that lysosomes are disrupted by a free radical-like factor produced during the oxidation of NADPH by liver microsomes that resulted in release of active acid hydrolases [11]
Summary
Since evidence had been published that lysosomes are disrupted by a free radical-like agent produced during the oxidation of NADPH by liver microsomes, the nature of this free radical was investigated. Aust and Pederson reported that the superoxide radical was apparently generated by an NADPH-cytochrome c reductase preparation from microsomes and that the radical may be responsible for lipid peroxidation [8] Their systems, required the addition of EDTA, which is a potent inhibitor of lipid peroxidation in biological materials [9], including the systems under study in this report. In lysosomal membranes, and apparently in certain membranous organelles, is initiated by hydroxyl free radicals derived from the activity of certain flavoenzymes and that the superoxide anion may possibly play a role in the formation of the OH.’ radicals These studies suggest that the activity of such flavin enzymes may contribute to the turnover of membrane polyunsaturated fatty acids and possibly initiate membrane lesions under some conditions. In order to simplify presentation of the data, only the results relating to acid phosphatase release are presented but the information is representative of the release of other lysosomal enzymes as well
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