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Anaesthesia Feb 2006Recent breakthroughs in molecular biology have enabled a reclassification of drug metabolising enzymes based on their amino acid sequence. This has led to a better... (Review)
Review
Recent breakthroughs in molecular biology have enabled a reclassification of drug metabolising enzymes based on their amino acid sequence. This has led to a better understanding of drug metabolism and drug interactions. The majority of these drug metabolising enzymes may be either induced or inhibited by drugs or by extraneous substances including foodstuffs, cigarette smoke and environmental pollutants. Virtually all drugs used in anaesthesia are metabolised by either hepatic phase 1 or phase II enzymes. This review considers the classification of drug metabolising enzymes, explains the mechanisms of enzyme induction and inhibition, and also considers how the action of drugs commonly used by anaesthetists, including opioids and neuromuscular blocking drugs, may be altered by this mechanism.
Topics: Analgesics, Opioid; Anesthetics; Animals; Biotransformation; Cytochrome P-450 Enzyme System; Drug Interactions; Enzyme Induction; Enzyme Inhibitors; Food-Drug Interactions; Humans; Liver; Smoking
PubMed: 16430569
DOI: 10.1111/j.1365-2044.2005.04462.x -
The AAPS Journal Jun 2008Induction of drug metabolizing enzymes, such as the cytochromes P450 (CYP) is known to cause drug-drug interactions due to increased elimination of co-administered... (Review)
Review
Induction of drug metabolizing enzymes, such as the cytochromes P450 (CYP) is known to cause drug-drug interactions due to increased elimination of co-administered drugs. This increased elimination may lead to significant reduction or complete loss of efficacy of the co-administered drug. Due to the significance of such drug interactions, many pharmaceutical companies employ screening and characterization models which predict CYP enzyme induction to avoid or attenuate the potential for drug interactions with new drug candidates. The most common mechanism of CYP induction is transcriptional gene activation. Activation is mediated by nuclear receptors, such as AhR, CAR, and PXR that function as transcription factors. Early high throughput screening models utilize these nuclear hormone receptors in ligand binding or cell-based transactivation/reporter assays. In addition, immortalized hepatocyte cell lines can be used to assess enzyme induction of specific drug metabolizing enzymes. Cultured primary human hepatocytes, the best established in vitro model for predicting enzyme induction and most accepted by regulatory agencies, is the predominant assay used to evaluate induction of a wide variety of drug metabolizing enzymes. These in vitro models are able to appropriately predict enzyme induction in patients when compared to clinical drug-drug interactions. Finally, transgenic animal models and the cynomolgus monkey have also been shown to recapitulate human enzyme induction and may be appropriate in vivo animal models for predicting human drug interactions.
Topics: Animals; Cell Line; Clinical Trials as Topic; Cytochrome P-450 Enzyme System; Drug Evaluation, Preclinical; Drug Industry; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Enzyme Induction; Hepatocytes; Humans; Transcriptional Activation
PubMed: 18686044
DOI: 10.1208/s12248-008-9037-4 -
The Journal of Steroid Biochemistry and... Jul 2013Cytochrome P450 3A4 (CYP3A4) is a multifunctional enzyme involved in both xenobiotic and endobiotic metabolism. This review focuses on two aspects: regulation of CYP3A4... (Review)
Review
Cytochrome P450 3A4 (CYP3A4) is a multifunctional enzyme involved in both xenobiotic and endobiotic metabolism. This review focuses on two aspects: regulation of CYP3A4 expression by vitamin D and metabolism of vitamin D by CYP3A4. Enterohepatic circulation of vitamin D metabolites and their conjugates will be also discussed. The interplay between vitamin D and CYP3A4 provides new insights into our understanding of how enzyme induction can contribute to vitamin D deficiency. This article is part of a Special Issue entitled 'Vitamin D Workshop'.
Topics: Animals; Biotransformation; Cytochrome P-450 CYP3A; Enterohepatic Circulation; Enzyme Induction; Humans; Models, Biological; Vitamin D; Vitamin D Deficiency
PubMed: 22985909
DOI: 10.1016/j.jsbmb.2012.09.012 -
Toxicology Letters Dec 1995Mammalian cells have evolved elaborate mechanisms for protection against the toxic and neoplastic effects of electrophilic metabolites of carcinogens and reactive oxygen... (Review)
Review
Mammalian cells have evolved elaborate mechanisms for protection against the toxic and neoplastic effects of electrophilic metabolites of carcinogens and reactive oxygen species. Phase 2 enzymes (e.g. glutathione transferase, NAD(P)H:quinone reductase, UDP-glucuronosyltransferases) and high intracellular levels of glutathione play a prominent role in providing such protection. Phase 2 enzymes are transcriptionally induced by low concentrations of a wide variety of chemical agents and such induction blocks chemical carcinogenesis. The inducers belong to many chemical classes including phenolic antioxidants. Michael reaction acceptors, isothiocyanates, 1,2-dithiole-3-thiones, trivalent arsenicals, HgCl2 and organomercurials, hydroperoxides, and vicinal dimercaptans. Induction by all classes of inducers involves the antioxidant/electrophile response element (ARE/EpRE). Inducers are widely, but unequally, distributed among edible plants. Search for such inducer activity in broccoli led to the isolation of sulforaphane, an isothiocyanate that is a very potent Phase 2 enzyme inducer and blocks mammary tumor formation in rats.
Topics: Animals; Anticarcinogenic Agents; Enzyme Induction; Glutathione Transferase; NAD(P)H Dehydrogenase (Quinone); Neoplasms; Plants; Rats
PubMed: 8597048
DOI: 10.1016/0378-4274(95)03553-2 -
Drug Metabolism Reviews Aug 2018Cytochrome P450 (P450, CYP) enzymes have long been of interest due to their roles in the metabolism of drugs, pesticides, pro-carcinogens, and other xenobiotic... (Review)
Review
Cytochrome P450 (P450, CYP) enzymes have long been of interest due to their roles in the metabolism of drugs, pesticides, pro-carcinogens, and other xenobiotic chemicals. They have also been of interest due to their very critical roles in the biosynthesis and metabolism of steroids, vitamins, and certain eicosanoids. This review covers the 22 (of the total of 57) human P450s in Families 5-51 and their substrate selectivity. Furthermore, included is information and references regarding inducibility, inhibition, and (in some cases) stimulation by chemicals. We update and discuss important aspects of each of these 22 P450s and questions that remain open.
Topics: Animals; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Enzyme Induction; Humans; Molecular Targeted Therapy; Pesticides; Xenobiotics
PubMed: 30717606
DOI: 10.1080/03602532.2018.1483401 -
British Journal of Clinical Pharmacology 1984All beta-adrenergic receptor blockers that require metabolism prior to elimination are potentially subject to drug interactions due to enzyme induction. However, data is...
All beta-adrenergic receptor blockers that require metabolism prior to elimination are potentially subject to drug interactions due to enzyme induction. However, data is only available in man for propranolol, metoprolol and alprenolol. Cross-sectional population studies suggest that environmental factors, such as smoking in the young, are able to influence the oral clearance of propranolol. Long-term studies comparing within-subject clearances of metoprolol, alprenolol and propranolol before and after rifampicin and pentobarbitone, indicate that oral clearance is increased by 50%-500%. Inducing agents can influence intrinsic clearance, liver blood flow, and protein binding in addition to drug metabolising ability, indicating that changes in pharmacokinetic disposition may be complex. Enzyme induction exhibits both dose and time dependency relationships. The maximal extent of enzyme induction is similar between subjects. The range of intersubject variation in drug metabolism is similar before and after induction. The reduction in steady-state beta-adrenergic receptor drug concentration following enzyme induction is sufficiently large that an altered pharmacodynamic response would be expected if no dosage modification is made.
Topics: Adolescent; Adrenergic beta-Antagonists; Adult; Aged; Antipyrine; Drug Interactions; Enzyme Induction; Half-Life; Humans; Kinetics; Middle Aged; Phenobarbital; Propranolol; Rifampin; Smoking
PubMed: 6146342
DOI: 10.1111/j.1365-2125.1984.tb02432.x -
British Medical Journal Nov 1976
Topics: Enzyme Induction; Glucaric Acid; Glutethimide; Humans; Male
PubMed: 990872
DOI: 10.1136/bmj.2.6046.1256-d -
Environmental Health Perspectives Apr 1987Biotransformation of xenobiotics in fish occurs by many of the same reactions as in mammals. These reactions have been shown to affect the bioaccumulation, persistence,... (Review)
Review
Biotransformation of xenobiotics in fish occurs by many of the same reactions as in mammals. These reactions have been shown to affect the bioaccumulation, persistence, residue dynamics, and toxicity of select chemicals in fish. P-450-dependent monooxygenase activity of fish can be induced by polycyclic aromatic hydrocarbons, but phenobarbital-type agents induce poorly, if at all. Fish monooxygenase activity exhibits ideal temperature compensation and sex-related variation. Induction of monooxygenase activity by polycyclic aromatic hydrocarbons can result in qualitative as well as quantitative changes in the metabolic profile of a chemical. Induction can also alter toxicity. In addition, multiple P-450 isozymes have been described for several fish species. The biotransformation products of certain chemicals have been related to specific P-450 isozymes, and the formation of these products can be influenced by induction. Exposure of fish to low levels of certain environmental contaminants has resulted in induction of specific monooxygenase activities and monitoring of such activities has been suggested as a means of identifying areas of pollutant exposure in the wild.
Topics: Animals; Biotransformation; Environmental Pollutants; Enzyme Induction; Fishes
PubMed: 3297653
DOI: 10.1289/ehp.8771105 -
The Journal of Clinical Psychiatry Jun 2012Smoking is associated with the induction of the CYP 1A2 enzyme, and hence with diminished levels of drugs metabolized by this enzyme. This article presents a...
Smoking is associated with the induction of the CYP 1A2 enzyme, and hence with diminished levels of drugs metabolized by this enzyme. This article presents a hypothetical patient, diagnosed with schizophrenia, who smokes about 10 cigarettes a day. The progress of the patient is examined across several follow up meetings, each of which presents a fresh clinical problem related to smoking and its interaction with the medication. Clinical guidance for each problem is presented along with a brief discussion on the subject. The article concludes with a discussion of other pharmacokinetic considerations related to smoking and its treatment in patients with schizophrenia.
Topics: Adult; Clozapine; Cytochrome P-450 CYP1A2; Enzyme Induction; Humans; Inactivation, Metabolic; Male; Schizophrenia; Schizophrenic Psychology; Smoking; Smoking Cessation
PubMed: 22795210
DOI: 10.4088/JCP.12f07732 -
Drug Metabolism and Disposition: the... Aug 2018The induction of cytochrome P450 (P450) enzymes in response to drug treatment is a significant contributing factor to drug-drug interactions, which may reduce...
The induction of cytochrome P450 (P450) enzymes in response to drug treatment is a significant contributing factor to drug-drug interactions, which may reduce therapeutic efficacy and/or cause toxicity. Since most studies on P450 induction are performed in adults, enzyme induction at neonatal, infant, and adolescent ages is not well understood. Previous work defined the postnatal ontogeny of drug-metabolizing P450s in human and mouse livers; however, there are limited data on the ontogeny of the induction potential of each enzyme in response to drug treatment. Induction of P450s at the neonatal age may also cause permanent alterations in P450 expression in adults. The goal of this study was to investigate the short- and long-term effects of phenytoin treatment on mRNA and protein expressions and enzyme activities of CYP2B10, 2C29, 3A11, and 3A16 at different ages during postnatal liver maturation in mice. Induction of mRNA immediately following phenytoin treatment appeared to depend on basal expression of the enzyme at a specific age. While neonatal mice showed the greatest fold changes in CYP2B10, 2C29, and 3A11 mRNA expression following treatment, the levels of induced protein expression and enzymatic activity were much lower than that of induced levels in adults. The expression of fetal CYP3A16 was repressed by phenytoin treatment. Neonatal treatment with phenytoin did not permanently induce enzyme expression in adulthood. Taken together, our data suggest that inducibility of drug-metabolizing P450s is much lower in neonatal mice than it is in adults and neonatal induction by phenytoin is not permanent.
Topics: Animals; Cytochrome P-450 Enzyme System; Enzyme Induction; Female; Gene Expression Regulation, Enzymologic; Liver; Male; Mice; Mice, Inbred C57BL; Phenytoin; RNA, Messenger
PubMed: 29884652
DOI: 10.1124/dmd.118.080861