Flowers N L, Miles P R
Applachian Laboratory for Occupational Safety and Health, Morgantown, WV 26505.
Toxicology. 1991;68(3):259-74. doi: 10.1016/0300-483x(91)90074-b.
Superoxide anion radical and hydrogen peroxide (H2O2) are reactive oxygen metabolites which are thought to be involved in oxidant-induced lung injuries. Therefore, we studied their effects on the pulmonary metabolism of benzo[a]pyrene (BP) in rat lung microsomes. The microsomes were incubated with xanthine and xanthine oxidase to generate superoxide anion (effects verified with superoxide dismutase) or H2O2 and then the products formed during the metabolism of BP were measured. Both oxygen metabolites inhibit BP hydroxylase activity, i.e., the production of 3- and 9-hydroxybenzo[a]pyrene (phenols) in a concentration-dependent manner. The phenols account for approximately 75% of metabolite formation and are the major products of BP metabolism. Two components of the monooxygenase system responsible for BP metabolism, cytochrome P-450 and NADPH-cytochrome P-450 reductase, are also inhibited by the two oxygen metabolites in a similar manner. Superoxide anion is more effective than H2O2 in the inhibition of both BP hydroxylase and the monooxygenase components. Neither oxygen metabolite has any effect on the formation of minor metabolites of benzo[a]pyrene, i.e., BP-quinones and BP-dihydrodiols. These are the BP metabolites thought to produce toxic effects and which may lead to the formation of carcinogens and/or mutagens. The results of all these experiments suggest that exposure of lung microsomes to oxygen metabolites can lead to a slowing of overall BP metabolism and the increased accumulation of potentially toxic BP metabolites.
超氧阴离子自由基和过氧化氢（H2O2）是活性氧代谢产物，被认为与氧化剂诱导的肺损伤有关。因此，我们研究了它们对大鼠肺微粒体中苯并[a]芘（BP）肺代谢的影响。将微粒体与黄嘌呤和黄嘌呤氧化酶一起孵育以生成超氧阴离子（用超氧化物歧化酶验证效果）或H2O2，然后测量BP代谢过程中形成的产物。两种氧代谢产物均以浓度依赖性方式抑制BP羟化酶活性，即3-和9-羟基苯并[a]芘（酚类）的产生。酚类约占代谢产物形成的75%，是BP代谢的主要产物。负责BP代谢的单加氧酶系统的两个组分，细胞色素P-450和NADPH-细胞色素P-450还原酶，也以类似方式被两种氧代谢产物抑制。在抑制BP羟化酶和单加氧酶组分方面，超氧阴离子比H2O2更有效。两种氧代谢产物对苯并[a]芘的次要代谢产物，即BP-醌和BP-二氢二醇的形成均无影响。这些是被认为会产生毒性作用并可能导致致癌物和/或诱变剂形成的BP代谢产物。所有这些实验的结果表明，肺微粒体暴露于氧代谢产物会导致BP整体代谢减慢以及潜在有毒BP代谢产物的积累增加。
