EFFECT OF ETHANOL ON P450 INDUCTION BY HOPS AND LUPULON

点击翻译按钮获取中文摘要

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.