The metabolism of benzene and phenol by a reconstituted purified phenobarbital-induced rat liver mixed function oxidase system.
The metabolism of benzene and phenol by a reconstituted purified phenobarbital-induced rat liver mixed function oxidase system.
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重建纯化苯巴比妥诱导的大鼠肝脏混合功能氧化酶系统对苯和苯酚的代谢。
DOI：
10.1007/978-1-4684-5134-4_18
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发表时间：
1986
影响因子：
--
通讯作者：
Snyder,R
中科院分区：
文献类型：
--
作者：
Griffiths,JC;Kalf,GF;Snyder,R
在其广泛的工业使用的悠久历史中，人类长期接触苯与血液疾病有关，例如再生障碍性贫血和白血病。我们的目标是研究苯的代谢与其产生骨髓毒性的机制之间的联系（Snyder 等，1967、1977、1982）。 Gonasun 等人证明了混合功能氧化酶是血红素蛋白细胞色素 P-450 酶家族，位于肝脏以及大多数其他组织的平滑内质网中。 (1973)在苯的代谢中发挥关键作用。 Jerina 和 Daly (1974) 以及 Tunek 等人的研究。 (1978) 强烈支持苯氧化物的形成是苯代谢的主要第一步的概念。然而，Ingelman-Sundberg 和 Hagbjork (1982) 提出，羟基化可能通过羟基自由基的插入而发生，假定是由“铁催化的细胞色素 P-450 依赖性 Haber Weiss 反应”产生的。 Gorsky 和 Coon (1984) 已经证明，苯的代谢途径与体外反应中使用的浓度直接相关，即，在非常低的浓度下，反应由游离羟基自由基机制介导，而在较高浓度的苯下，在其 KM 范围内，通过直接细胞色素 P-450 介导的氧化。如果（1）有两种（或更多）细胞色素 P-450 参与羟基化，一种能够形成环氧化物中间体，另一种能够通过 Haber Weiss 机制产生自由基，或者（2）负责环氧化的细胞色素 P-450 也起到 NADPH 氧化酶的作用，从而产生 H2O2，随后产生羟基自由基，则这两个概念可以协调一致。 Post 和 Snyder (1983) 最近报告的证据表明，至少有两种不同的大鼠肝脏混合功能氧化酶在苯的羟基化中具有活性。使用从苯巴比妥诱导的大鼠肝脏中重建纯化的混合功能氧化酶系统，我们研究了苯代谢中导致苯酚形成的初始羟基化步骤以及苯酚随后转化为多羟基化代谢物。
During its long history of extensive industrial use, chronic exposure of humans to benzene has been associated with blood disorders, such as aplastic anemia and leukemia. It has been our aim to study the link between the metabolism of benzene and the mechanism by which it produces bone marrow toxicity (Snyder et al., 1967, 1977, 1982). The mixed function oxidases, a family of hemoprotein cytochrome P-450 enzymes located in the smooth endoplasmic reticulum of liver as well as most other tissues, was shown by Gonasun et al. (1973) to play a key role in the metabolism of benzene. Studies by Jerina and Daly (1974) and Tunek et al. (1978) strongly supported the concept that the formation of benzene oxide is the principal first step in benzene metabolism. However, Ingelman-Sundberg and Hagbjork (1982) have suggested that the hydroxylation may occur via the insertion of a hydroxyl free radical, postulated to be generated from an “iron-catalyzed cytochrome P-450-dependent Haber Weiss reaction.” Gorsky and Coon (1984) have demonstrated that the pathway by which benzene is metabolized is directly related to the concentration utilized in thein vitroreaction, i.e. with very low concentrations the reaction is mediated by a free hydroxyl-radical mechanism and at higher concentrations of benzene, in the range of its KM, by direct cytochrome P-450-mediated oxidation. These two concepts could be reconciled if (1) there were two (or more) cytochromes P-450 involved in the hydroxylation, one with the ability to form an epoxide intermediate and another generating free radicals through a Haber Weiss mechanism, or (2) the cytochrome P-450 responsible for epoxidation also functioned as a NADPH oxidase, thereby, producing H2O2which subsequently generated the hydroxyl radicals. Post and Snyder (1983) recently reported evidence which suggested that there are at least two different rat liver mixed function oxidases active in the hydroxylation of benzene. Using a reconstituted purified mixed function oxidase system from phenobarbital-induced rat liver, we have studied the initial hydroxylation step in benzene metabolism leading to phenol formation and the subsquent conversion of phenol to polyhydroxylated metabolites.