EFFECT OF ETHANOL ON P450 INDUCTION BY HOPS AND LUPULON

肝脏细胞色素P-450系统参与了 大多数药物和其他外来物质的生物转化。 由大量药物和其他物质诱导的这一系统 外源生物在药物治疗、药物毒性、 致癌和诱变。发现了一种粗暴的商业饮食 在小鼠中支持更高水平的P-450系统 由酪蛋白、淀粉、玉米油和 必需的矿物质和维生素。对个人的检查 粗饲料的成分显示，酿酒酵母是 P-450系统的主要诱导者。人们的注意力集中在啤酒花上 当研究表明，在没有酒花的情况下生长的酵母是 不能作为P-450系统的诱导剂。在随后的研究中 结果表明，啤酒花中的树脂组分 作为酿酒行业的β-酸级分，极大地诱导 P-450系统的组成和多种P-450依赖的 单加氧酶反应。一种高纯度的β酸级分 主要由天然抗生素卢普隆组成，证明了 成为这个体系的有力诱导者。-450系统包括 由几种同工酶组成，每一种都有宽广的、重叠的底物 选择性。P-450亚群的新的和变化的模式是 在给予某些类型的诱导剂时产生。 因此，苯巴比妥(PB)、3-甲基胆蒽(MC)、类固醇和 乙醇诱导不同的P-450同工酶和 单加氧酶活性。诱导通常会降低毒性。 药物和其他外源物质，但MC类型的诱导 增加化学致癌和致突变；乙醇 诱导导致常用药物对乙酰氨基酚 代谢成一种会导致慢性肝损伤的产品 乙醇的消费者。提出了三个研究项目： 项目1将尝试描述归纳的类型 由羽扇豆酒、啤酒花、酿酒酵母和啤酒生产。这将是 通过a)比较以下各项的诱导效果来完成 物质与各种经典诱导剂(PB，MC， PCN、乙醇、异沙芬、氯纤维蛋白)与它们的 诱导一组P-450连接的单加氧酶反应；b) 通过比较它们诱导的P-450细胞的凝胶电泳性 诱导剂；c)使用针对诱导剂的选择性抗体。 项目2将确定羽扇豆或啤酒花是否诱导形成(S) 产生苯并(A)苯与DNA共价结合的P-450，a 启动致癌的过程。项目3将评估 羽扇豆隆和啤酒花对妊娠和非妊娠小鼠的毒性 为期4周。这些研究的目的是预测 或者当啤酒花的成分被 通过酿酒酵母和啤酒引入饮食。

The hepatic cytochrome P-450 system is involved in the biotransformation of most drugs and other foreign substances. Induction of this system by a large number of drugs and other xenobiotics plays an important role in drug therapy, drug toxicity, carcinogenesis and mutagenesis. A crude commercial diet was found to support a much higher level of the P-450 system in mice than a purified commerical diet consisting of casein, starch, corn oil and essential minerals and vitamins. Examination of individual ingredients of the crude diet revealed that brewers yeast was the major inducer of the P-450 system. Attention was focused on hops when it was shown that yeast grown in the absence of hops was inactive as an inducer of the P-450 system. In subsequent studies it was shown that the resin fraction of hops, refered to in the brewing industry as the beta-acid fraction, greatly induced components of the P-450 system and a variety of P-450-dependent monooxygenase reactions. A highly purified beta acid-fraction consisting essentially of the natural antibiotic, lupulon, proved to be a potent inducer of the system. The-450 system is comprised of several isozymes, each with broad, overlapping substrate selectivities. New and varied patterns of P-450 subsets are created when certain types of inducing agents are administered. Thus phenobarital (PB), 3-methylcholanthene (MC), steroids, and ethanol induce different patterns of P-450 isozymes and monooxygenase activities. Induction usually decreases the toxicity of drugs and other xenobiotics, but the MC-type of induction increases chemical carcinogenesis and mutagenesis; ethanol induction causes the commonly used drug, acetaminophen, to be metabolized to a product that causes severe liver damage in chronic consumers of ethanol. Three research projects are proposed: Project 1 will attempt characterization of the kind of induction produced by lupulon, hops, brewers yeast and beer. This will be accomplished by a) comparing the inductive effects of these substances with a variety of classical inducing agents (PB, MC, PCN, ethanol, isosaffrole, clofibrin) with respect to their induction of a battery of P-450-linked monooxygenase reactions; b) by comparing gel electrophoresis of P-450s induced by these inducers; c) by employing selective antibodies against inducers. Project 2 will determine if lupulon or hops induces the form(s) of P-450 that generate covalent binding of benzo(a)benzene to DNA, a process that initiates carcinogenesis. Project 3 will evaluate the toxicity of lupulon and hops fed to pregnant and non-pregnant mice for 4 weeks. These studies are intended to predict what beneficial or toxic effects are likely to occur when components of hops are introduced into the diet via brewers yeast and beer.