CYTOCHROME-P-450 SPIN STATE AND LEAKINESS OF THE MONOOXYGENASE PATHWAY
CYTOCHROME-P-450 SPIN STATE AND LEAKINESS OF THE MONOOXYGENASE PATHWAY
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DOI：
10.3109/00498259109039456
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发表时间：
1991-01-01
期刊：
影响因子：
1.8
通讯作者：
RUCKPAUL, K
中科院分区：
文献类型：
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作者：
BLANCK, J;RISTAU, O;RUCKPAUL, K
1. 研究了苯非他明类似物诱导铁细胞色素P-450高自旋位移（delta - α）对苯巴比妥（PB）处理家兔肝微粒体单加氧酶和氧化酶活性的影响。通过第一电子转移动力学，底物的自旋位移活性决定了反应中间体氧细胞色素P-450的稳态水平。氧细胞色素P-450的量与δ - α的相关性可以通过实验证明。氧细胞色素P-450的自旋状态依赖性形成定量调节NADPH氧化和底物n-去甲基化的速率。这两种活动都与δ - α有关。氧细胞色素P-450是底物稳定的，随着O2的形成而衰变。-突变后生成H2O2.4。n -去甲基化酶与NADPH氧化酶活性的比值（偶联比）也随着自旋位移δ α而增加。同时，通过二电子还原和四电子还原生成H2O2和H2O所占的NADPH比例降低。这表明底物引起的酶活性中心的结构变化引起自旋跃迁，同样可能改变偶联性质。未进行单氧合的全氟化合物在NADPH氧化速率和稳态氧化细胞色素P-450水平对δ - α的依赖性方面与苯非他明衍生物一致。氧化酶活性的增加主要是由于水的形成。在苯非他明和全氟化合物存在的情况下，铅诱导的单加氧酶途径在氧的生物转化过程中漏出，不会导致水的形成明显增加。因此，这些底物增加NADPH氧化酶活性并没有显著增强h2o2介导的氧组织毒性。
1. The monooxygenase and oxidase activities of liver microsomes from phenobarbital (PB)-treated rabbits were investigated for their dependence on the high spin shift (DELTA-alpha) of the ferric cytochrome P-450 induced by a series of benzphetamine analogues.2. The spin shift activity of the substrate determines, via the first electron transfer kinetics, the steady-state level of the reaction intermediate oxycytochrome P-450. Correlation of the amount or oxycytochrome P-450 with DELTA-alpha can be experimentally proved.3. The spin-state-dependent formation of oxycytochrome P-450 regulates quantitatively the rates of NADPH oxidation and substrate N-demethylation. Both activities correlate with DELTA-alpha. Oxycytochrome P-450 is substrate-stabilized towards decay with the formation of O2.- which, upon dismutation, gives rise to H2O2.4. The ratio of N-demethylase to NADPH oxidase activity (coupling ratio) also increases with the spin shift, DELTA-alpha. Concomitantly, the proportion of NADPH accounted for by H2O2 and H2O formation via two-and four-electron reduction of dioxygen decreases. This indicates that the substrate-induced structural changes in the enzyme active centre which give rise to spin transition may likewise modify the coupling properties.5. Perfluorinated compounds, which fail to undergo monooxygenation, fall in line with the benzphetamine derivatives with respect to the dependence of NADPH oxidation rate and steady-state oxycytochrome P-450 level on DELTA-alpha. The increased oxidase activity results mostly in H2O formation.6. The leakiness of the PB-induced monooxygenase pathway in the biotransformation of oxygen in the presence of the benzphetamines and perfluorinated compounds does not result in marked increases in H2O formation. Therefore, the increase of NADPH oxidase activity by these substrates does not significantly enhance H2O2-mediated oxygen tissue toxicity.