Cyp2e1 is the principal p450 responsible for the metabolism of. They will also function as an important in vivo tool for predicting drug metabolism and disposition and drug drug interactions of chemicals that are substrates for human cyp2e1. The liver is therefore where most drugs undergo deactivation by cyp2e1, either directly or by facilitated excretion from the body. Construction of a cyp2e1template system for prediction of. Preclinical drug metabolism and pharmacokinetics studies play a key role in lead identification and. The role of cyp2e1 in alcohol metabolism and sensitivity.
Cyp2c8 is highly expressed in human liver and is known to metabolize more than 100 drugs. The liver is therefore where most drugs undergo deactivation by cyp2e1. These results indicate that hepatic cyp2e1 mainly contributes to maos in rats and humans, the pathway of which may play an alternative role against acetaldehyde in the liver after alcohol consumption together with acetaldehyde dehydrogenase in the metabolism of acetaldehyde. Contribution of cyp2e1 and cyp3a to acetaminophen reactive. Specifically, cyp2e1 has been implicated in different brain pathologies, possibly due to its role as a drug metabolism. Pdf isozymeselective metabolism of ethyl carbamate by. Further research is needed to determine the scope, magnitude and clinical importance of food effects on drug metabolism and transport. Accordingly, cmx001 has no risk for ddi with drugs that modulate the activity of cyp3a, 2c8, 2c19 and 2e1, nor any of the other major drug metabolizing enzymes, including. Gilmans manual of pharmacology and therapeutics, mcgraw. The general intention is to demonstrate that the metabolism of a drug is a primary concern throughout. This chapter focuses on the discussion of cyp2e1 in ethanol metabolism in the cns, covering topics including how it is regulated, where it is expressed and how it influences sensitivity to ethanol in the brain. In addition, it is involved in the metabolism of drugs such as acetaminophen. Table showing examples of anaesthetic drug metabolism by cytochrome p450 system phases of metabolism metabolism of drugs is usually divided into phase 1 and phase 2. Acetaldehyde as well as ethanol is metabolized by human cyp2e1.
Cyp enzyme activity is differentially affected by the presence of tumour. Cyp2a2, cyp3a1, cyp1b1, cyp2b1, cyp2b2, cyp2c1, cyp2c6, cyp2e1 can be inhibited by some vegetables. Cyp2e1 and glutathione transferase loci s gstm1 and gstt1 are involved in the metabolism of isoniazid, the most toxic drug for the treatment of tuberculosis tb. Pharmacokinetic consequences of induction of cyp2e1 by ligand stabilization. We rely on drug metabolism when we dose and would like to treat every individual the same way.
Cytochrome p450 2e1 cyp2e1 is a major component of the microsomal ethanoloxidizing system meos, and is responsible for about 10% of total ethanol metabolism. Since its inception, the goal of the handbook was to provide a comprehensive text to serve as a graduate course in drug metabolism, a useful reference for academic and industrial drug metabolism scientists, but also as an important reference tool for those pursuing a career in drug discovery and. Cyp2e1 and oxidant stress in alcoholic and nonalcoholic fatty liver. Production of deramciclane metabolites was significantly inhibited by diethyldithiocarbamate and was elevated in liver microsomes of isoniazidtreated rats. Cyp2e1, cyp2a6 and cyp3a5 enzymes belong to phase i group of drug. Investigation of xenobiotics metabolism, genotoxicity, and carcinogenicity using cyp2e1 mice authors.
Drug interactions with tobacco smoking springerlink. Presence of polymorphisms in the genes coding for these enzymes results in interindividual variations in drug metabolism, therapeutic response and susceptibility towards various. Pharmacokinetic interactions occur when alcohol alters the metabolism or excretion of the drug or vice versa. Investigation of xenobiotics metabolism, genotoxicity, and. Cyp3a4, 1a2, 2c9, 2c19, 2d6, 2e1 are the major p450s that are involved in drug metabolism and catalyze the oxidation of almost 90% of human drugs104. We always associate the liver as the major organ responsible for. Although several cytochrome p450 forms were involved in the metabolism, the role of cyp2e1 should be emphasized, since it catalyzed almost all steps. The role of cyp2e1 in the drug metabolism or bioactivation in the brain. Drug metabolism drug metabolism is the metabolic breakdown of drugs which is catalyzed by drug metabolizin g enzymes and consists of two phases, phase i and ii.
Tributyltin has been found to inhibit the function of cytochrome p450, leading to masculinization of mollusks. It is almost a decade since the second edition of the handbook of drug metabolism was published. Antihypertensives, antidiabetics, statins, analgesics and antipsychotics were the most common drugs interacting with fruits and vegetables. Cytochrome p450mediated drug metabolism in the brain. Cyp2c8 substrate drugs include amodiaquine, cerivastatin, dasabuvir, enzalutamide, imatinib, loperamide, montelukast, paclitaxel, pioglitazone, repaglinide, and rosiglitazone, and the. Relationship with oxidative stress and smoking habit. During the last 1015 years, cytochrome p450 cyp 2c8 has emerged as an important drug metabolizing enzyme. Organisms have metabolic pathways that are responsible for removing toxic agents.
They are involved in the metabolism of most medications and are the mechanism by which most pharmacokinetic drug interactions occur. Cyp4f2 is the major cytochrome p450 enzyme involved in. In vitro studies suggested that cyp2e1 is the principal highaffinity enzyme responsible for tce metabolism. Pdf organisms have metabolic pathways that are responsible for removing toxic agents. This study was designed to determine the frequency and to evaluate whether polymorphisms at cyp2e1, gstm1 and gstt1 genes.
Cyp2e1 humanized mice will be of great value for delineating the role of human cyp2e1 in ethanolinduced oxidative stress and alcoholic liver damage. Strategies for in vitro metabolic stability testing. Effect of fruitvegetabledrug interactions on cyp450. Cyp2e1 epigenetic regulation in chronic, lowlevel toluene exposure.
P450 drug metabolism i 20 university of washington. Pdf pharmacokinetic consequences of induction of cyp2e1. Role of cytochrome p450 2c8 in drug metabolism and. The role of cyp2e1 in the drug metabolism or bioactivation in the. Role of cyp2e1 in the hepatotoxicity of acetaminophen. P450s were proposed to be involved in the oxidization of hz and achz to reactive metabolites 16, 56, 58. The objective of the present work is to more directly assess the role of cyp2e1 in the metabolism and disposition of 1,214ctce administered at 250 or mgkg gavage using cyp2e1 knockout ko versus wildtype wt mice. Strategies for in vitro metabolic stability testing christopher patten, phd bd biosciences december 2, 2009. Drugs for which induced metabolism because of cigarette smoking may have clinical consequence include theophylline, caffeine, tacrine, imipramine, haloperidol, pentazocine, propranolol, flecainide and estradiol. A primer for bioanalytical chemists, part i in the face of advancing technology in combinatorial synthesis and high throughput screening, the drug discovery process continues to evolve.
Patient variability largely due to differences in drug metabolism capacity. Alcoholrelated drug interactions many drugs interact with alcohol resulting in undesirable outcomes. Pdf the role of cyp2e1 in the drug metabolism or bioactivation. Cyp2e1 is a membrane protein expressed in high levels in the liver, where it composes nearly 50% of the total hepatic cytochrome p450 mrna and 7% of the hepatic cytochrome p450 protein. Cyp2e1 is inducible by ethanol and other low molecular weight substrates5, 12. Other important cyp450 enzymes include cyp1a2, cyp2c9, cyp2c19, and cyp2d6. Although phase i drug metabolism occurs in most tissues, the primary and first pass site of metabolism occurs during hepatic circulation.
Cytochrome p450 cyp enzymes are key components in drug metabolism and xenobiotic induced toxicity. Recently, interactions involving drug transporters, including pglycoprotein and the organic anion transporting polypeptide, have also been identified. The cytochrome p450 super family is a group of hemecontaining proteins with multiple functions including the metabolism of xenobiotics such as drugs, toxins. Cyp2e1 is developmentally regulated, under liverspecific control. Cytochrome p450 cyp2e1 is a key player in the metabolism of endogenous substrates, including acetone and fatty acids and exogenous compounds, such as anaes thetics, ethanol, chlorzoxazone, tetrachloride, nicotine and paracetamol usan. Plasma exosomes exacerbate alcohol and acetaminophen. Watercress is also a known inhibitor of the cytochrome p450 cyp2e1, which may result in altered drug metabolism for individuals on certain medications e. Biotransformation the elimination of xenobiotics often depends on their conversion to watersoluble chemicals through biotransformation, catalyzed by multiple enzymes primarily in the liver with contributions from. Contribution of cyp2e1 and cyp3a to acetaminophen reactive metabolite formation.
Some complications of drug therapy that are due to variability in metabolism. The mechanism involved in most interactions between cigarette smoking and drugs involves the induction of metabolism. Metabolism and exposure markers section, laboratory of pharmacology and chemistry, national toxicology program, national institute of environmental health sciences,national institutes of health, rtp, nc. Abstractcytochrome p450 2e1 cyp2e1 plays a vital role in druginduced. The metabolism of endogenous compounds and 90% of exogenous drugs currently in use are governed by the highly polymorphic enzyme, cytochrome p450 cyp450 4. According to pain guidelines in children, the latter. Specifically, cyp2e1 has been implicated in different brain pathologies, possibly due to its role as a drug metabolism or activator enzyme. Background cyp2e1, 1a2, and 3a4 have all been implicated in the formation of n. Cyp2e1 sevoflurane, isoflurane, halothane cyp3a4 midazolam, fentanyl, alfentanil, lidocaine, ketamine table 1. Cyp2e1 is an enzyme that particularly participates in the metabolism of endogenous substrates, including acetone. View the article pdf and any associated supplements and figures for a period of 48 hours. Subsequent studies revealed that activation of acetaminophen to an active metabolite is primarily carried out by cyp2e1, an ethanolinducible cytochrome p450 that was first suggested by characterization of the microsomal ethanol oxidation system. Production of deramciclane metabolites was significantly inhibited by diethyldithiocarbamate and was elevated in.
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