SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions (original) (raw)
Related papers
Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry
Naunyn-Schmiedeberg's Archives of Pharmacology, 2004
Of about one dozen human P450 s that catalyze biotransformations of xenobiotics, CYP2D6 is one of the more important ones based on the number of its drug substrates. It shows a very high degree of interindividual variability, which is primarily due to the extensive genetic polymorphism that influences expression and function. This so-called debrisoquine/sparteine oxidation polymorphism has been extensively studied in many different populations and over 80 alleles and allele variants have been described. CYP2D6 protein and enzymatic activity is completely absent in less than 1% of Asian people and in up to 10% of Caucasians with two null alleles, which do not encode a functional P450 protein product. The resulting "poor metabolizer" (PM) phenotype is characterized by the inability to use CYP2D6-dependent metabolic pathways for drug elimination, which affect up to 20% of all clinically used drugs. The consequences are increased risk of adverse drug reactions or lack of therapeutic response. Today, genetic testing predicts the PM phenotype with over 99% certainty. At the other extreme, the "Ultrarapid Metabolizer" (UM) phenotype can be caused by alleles carrying multiple gene copies. "Intermediate Metabolizers" (IM) are severely deficient in their metabolism capacity compared to normal "Extensive Metabolizers" (EM), but in contrast to PMs they express a low amount of residual activity due to the presence of at least one partially deficient allele. Whereas the intricate genetics of the CYP2D6 polymorphism is becoming apparent at ever greater detail, applications in clinical practice are still rare. More clinical studies are needed to show where patients benefit from drug dose adjustment based on their genotype. Computational approaches are used to predict and rationalize substrate specificity and enzymatic properties of CYP2D6. Pharmacophore modeling of ligands and protein homology mod-eling are two complementary approaches that have been applied with some success. CYP2D6 is not only expressed in liver but also in the gut and in brain neurons, where endogenous substrates with high-turnover have been found. Whether and how brain functions may be influenced by polymorphic expression are interesting questions for the future.
The pharmacology of the cytochrome P450 enzyme system
1998
The cytochrome P450 enzymes are a family of haem-oxygenases that are ubiquitously distributed throughout nature and subserve a variety of metabolic functions in man. They are the products of a gene superfamily comprising over 400 members. In man, four families (comprising about 20 major isoforms) are responsible for most of the oxidative drug metabolism which occurs primarily in the liver but which may also occur to a significant extent in other tissues. The enzymes are capable of inserting a single atom of oxygen into a vast number of structurally unrelated compounds, which explains the unique versatility of this enzyme system. This lack of substrate specificity may lead to substrate competition and thus drug interactions by enzyme inhibition. Several polymorphisms in the genes coding for P450s have been identified which may cause inter-individual variation in rates of drug metabolism, and hence therapeutic response, and in some cases, toxicity. This review describes recent advances in the pharmacology of the P450 enzymes and highlights the role of this versatile drug-oxidizing system in drug response, drug toxicity and drug interactions.
Polymorphic Cytochrome P450 Enzymes (CYPs) and Their Role in Personalized Therapy
PLoS ONE, 2013
The cytochrome P450 (CYP) enzymes are major players in drug metabolism. More than 2,000 mutations have been described, and certain single nucleotide polymorphisms (SNPs) have been shown to have a large impact on CYP activity. Therefore, CYPs play an important role in inter-individual drug response and their genetic variability should be factored into personalized medicine. To identify the most relevant polymorphisms in human CYPs, a text mining approach was used. We investigated their frequencies in different ethnic groups, the number of drugs that are metabolized by each CYP, the impact of CYP SNPs, as well as CYP expression patterns in different tissues. The most important polymorphic CYPs were found to be 1A2, 2D6, 2C9 and 2C19. Thirty-four common allele variants in Caucasians led to altered enzyme activity. To compare the relevant Caucasian SNPs with those of other ethnicities a search in 1,000 individual genomes was undertaken. We found 199 non-synonymous SNPs with frequencies over one percent in the 1,000 genomes, many of them not described so far. With knowledge of frequent mutations and their impact on CYP activities, it may be possible to predict patient response to certain drugs, as well as adverse side effects. With improved availability of genotyping, our data may provide a resource for an understanding of the effects of specific SNPs in CYPs, enabling the selection of a more personalized treatment regimen.
Cytochrome P450 Part 1: Multiplicity and Function
Journal of Pharmacy Practice and Research, 2008
While new cytochrome P450 (CYP450) enzymes continue to be identified, it is now possible to predict with some confidence the total number of human CYP450 enzymes. This review is an update of the CYP450 superfamily of drug metabolising enzymes. It comprises a brief history of CYP450 research, outlines the standard P450 nomenclature system, and describes CYP450 multiplicity, structure and function. J Pharm Pract Res 2008; 38: 55-7.
Journal of Molecular Catalysis B: Enzymatic, 2010
Inhibitors of some cytochrome P450s (CYPs) are used to design target-specific drugs. CYPs belonging to families 1-4 play important roles in drug metabolism and therapeutics. Some isozymes of CYPs also activate pro-carcinogens into their carcinogenic forms. Approximately 40-50% human CYP-dependent drug metabolism is carried out by polymorphic CYPs resulting in therapeutic failure and adverse reactions. Phenotyping of CYPs involved in the metabolism of a drug is important to understand the potential of clinical interactions and to predict the possible individual variations due to genetic polymorphisms of certain CYPs.
a r t i c l e i n f o Keywords: Biotransformation Cytochrome P450 monooxygenase NADPH:cytochrome P450 reductase Pharmacogenetics Polymorphism Xenobiotic Cytochromes P450 (CYP) are a major source of variability in drug pharmacokinetics and response. Of 57 putatively functional human CYPs only about a dozen enzymes, belonging to the CYP1, 2, and 3 families, are responsible for the biotransformation of most foreign substances including 70-80% of all drugs in clinical use. The highest expressed forms in liver are CYPs 3A4, 2C9, 2C8, 2E1, and 1A2, while 2A6, 2D6, 2B6, 2C19 and 3A5 are less abundant and CYPs 2J2, 1A1, and 1B1 are mainly expressed extrahepatically. Expression of each CYP is influenced by a unique combination of mechanisms and factors including genetic polymorphisms, induction by xenobiotics, regulation by cytokines, hormones and during disease states, as well as sex, age, and others. Multiallelic genetic polymorphisms, which strongly depend on ethnicity, play a major role for the function of CYPs 2D6, 2C19, 2C9, 2B6, 3A5 and 2A6, and lead to distinct pharmacogenetic phenotypes termed as poor, intermediate, extensive, and ultrarapid metabolizers. For these CYPs, the evidence for clinical significance regarding adverse drug reactions (ADRs), drug efficacy and dose requirement is rapidly growing. Polymorphisms in CYPs 1A1, 1A2, 2C8, 2E1, 2J2, and 3A4 are generally less predictive, but new data on CYP3A4 show that predictive variants exist and that additional variants in regulatory genes or in NADPH: cytochrome P450 oxidoreductase (POR) can have an influence. Here we review the recent progress on drug metabolism activity profiles, interindividual variability and regulation of expression, and the functional and clinical impact of genetic variation in drug metabolizing P450s.
Unlocking the Clinical Significance of Cytochrome P450 Enzymes
International journal of pharmaceutical investigation, 2023
Aim/Background: The Cytochrome P450 (CYP) enzyme family, consisting of 57 distinct genes, plays a pivotal role in various biological processes. These genes encode enzymes with multifaceted functions, impacting vital processes like arachidonic acid metabolism, xenobiotic detoxification, eicosanoids production, and drug metabolism. Moreover, CYP enzymes are indispensable for the synthesis of bile acids, steroids, and numerous metabolic pathways. They also participate in the hydroxylation of retinoic acid, illustrating their remarkable versatility. While some CYP enzymes still have undiscovered functions, their role continues to captivate researchers across diverse domains. Additionally, mutations in CYP genes can give rise to inborn metabolic disorders, leading to clinically significant diseases, underscoring the importance of CYP enzymes in maintaining metabolic equilibrium and overall well-being. Beyond their initial association with hepatic drug detoxification, recent research has unveiled a broader spectrum of enzymatic processes undertaken by cytochrome P450. The complexity of CYP enzymes is progressively unfolding, emphasizing their clinical significance and opening new avenues for drug development, precision medicine, and patient care. methodology: This abstract presents a comprehensive overview of the literature on cytochrome P450 enzymes and their diverse functions. The information was gathered from a wide range of sources, including scientific articles, textbooks, and research publications. The analysis covers the genetic basis of CYP enzymes, their roles in various metabolic pathways, and the clinical implications of CYP gene mutations. Additionally, the abstract highlights the recent advances in our understanding of CYP enzymes and their expanding role in maintaining human life. Results: The results of this study showcase the remarkable diversity of functions performed by cytochrome P450 enzymes. They are intricately involved in processes critical to human health, ranging from drug metabolism to the synthesis of vital biomolecules. The study underlines the clinical significance of CYP enzymes, as mutations in these genes can lead to severe metabolic disorders and diseases. Furthermore, it emphasizes the evolving understanding of CYP enzyme complexity and its implications for drug development, precision medicine, and patient care. Conclusion: In conclusion, this abstract sheds light on the exceptional versatility and clinical importance of cytochrome P450 enzymes. Their diverse functions have far-reaching consequences for human health, making them a focal point of research in pharmacology and medicine. The evolving understanding of CYP enzyme complexity paves the way for future advancements in drug development and personalized patient care, offering new possibilities for enhancing the well-being of individuals and populations. This research underscores the significance of CYP enzymes and their potential to revolutionize the fields of medicine and pharmacology.
Discerning Relationships Among Human Cytochrome P450s by Computational Analyses
Cytochrome P450s are involved in the biotransformations and metabolism of wide variety of xenobiotics and are essential players in the metabolism of pharmaceuticals and their role in drug-drug interactions. Here the authors have attempted to reveal their structure-function and evolutionary relationships of six major human P450s (CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP1A2 and CYP2E1) using some of the current computational tools available. These six isoforms are responsible for metabolism of over 90% of drugs and xenobiotics in humans. The computational analyses performed corroborate literature findings and, in addition, have revealed information that could be exploited to explain the functional differences between these enzymes.
Cytochrome P450 Part 3: Impact of Drug-Drug Interactions
Journal of Pharmacy Practice and Research, 2009
The role of individual hepatic cytochrome P450 (CYP) enzymes in drug metabolism and the factors that modulate CYP activity are becoming increasingly well understood. These advances have resulted in a better understanding of drug-drug and drugfood interactions and an enhanced capacity to predict drug interactions that may occur with new drugs. This final article in the series describes the issues and principles that are important in identifying and assessing drug interactions that involve CYP enzymes.