CYTOCHROME P450-MEDIATED TOXICITY OF THERAPEUTIC DRUGS (original) (raw)
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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.
The role of cytochrome P450 enzymes in hepatic and extrahepatic human drug toxicity
Pharmacology & Therapeutics, 1995
The human cytochrome P450 enzyme system metabolises a wide array of xenobiotics to pharmacologically inactive metabolites, and occasionally, to toxicologically active metabolites. Impairment of cytochrome P450 activity, which may be either genetic or environmental, may lead ta toxicity caused by the parent compound itself. In practise, this usually only applies to drugs that have a narrow therapeutic index and when their clearance is critically dependent upon the fraction normally metabolised by that pathway. P450 enzymes may also convert the drug to a chemically reactive metabolite, which, if not detoxified, may lead to various forms of hepatic and extrahepatic toxicity, including cellular necrosis, hypersensitivity, teratogenicity, and carcinogenicity, depending on the site of formation and the relative stability of the metabolite, and the cellular macromolecule with which it reacts. Variation in the regulation and expression of the drug metabolising enzymes may play a key role in both interindividual variation in sensitivity to drugltoxicity and tissue-specific damage. Avoidance of toxicity may be possible in ram instances by prediction of individual susceptibility or by designing new chemical entities that are metabolised by a range of enzymes (both cytochromes P450 and others) and do not undergo bioactivation.
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.
Cytochromes P450 and experimental models of drug metabolism
Journal of Cellular and Molecular Medicine, 2002
For the development of new drugs, evaluation of drug-drug interactions with already known compounds, as well as for better understanding of metabolism pathways of various toxicants and pollutants, we studied the drug metabolism mediated by cytochromes P450. The experimental approach is based on animal drug-metabolising systems. From the ethical as well as rational reasons, the selection of an appropriate system is crucial. Here, it is necessary to decide on the basis of expected CYP system involved. For CYP1A-mediated pathways, all the commonly used experimental models are appropriate except probably the dog. On the contrary, the dog seems to be suitable for modelling of processes depending on the CYP2D. With CYP2C, which is possibly the most large and complicated subfamily, the systems based on monkey (Maccacus rhesus) may be a good representative. The CYP3A seems to be well modelled by pig or minipig CYP3A29. Detailed studies on activities with individual isolated CYP forms are needed to understand in full all aspects of inter-species differences and variations.
Inhibition and induction of human cytochrome P450 enzymes: current status
Archives of Toxicology, 2008
Variability of drug metabolism, especially that of the most important phase I enzymes or cytochrome P450 (CYP) enzymes, is an important complicating factor in many areas of pharmacology and toxicology, in drug development, preclinical toxicity studies, clinical trials, drug therapy, environmental exposures and risk assessment. These frequently enormous consequences in mind, predictive and pre-emptying measures have been a top priority in both pharmacology and toxicology. This means the development of predictive in vitro approaches. The sound prediction is always based on the firm background of basic research on the phenomena of inhibition and induction and their underlying mechanisms; consequently the description of these aspects is the purpose of this review. We cover both inhibition and induction of CYP enzymes, always keeping in mind the basic mechanisms on which to build predictive and preventive in vitro approaches. Just because validation is an essential part of any in vitro-in vivo extrapolation scenario, we cover also necessary in vivo research and findings in order to provide a proper view to justify in vitro approaches and observations.
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.
Cytochrome P450 – Role In Drug Metabolism And Genetic Polymorphism
2018
The cytochrome P450 isoenzymes are a super family of haemoproteins that are terminal oxidases of mixed function oxidase system embedded primarily in the lipid bilayer of the endoplasmic reticulum (ER) of hepatocytes. They are so named because they are bound to membrane within a cell (cyto) and contain a haeme pigment (chrome P) that absorb light at a wavelength 450 nm when exposed to carbon monoxide. They are essential for metabolism of large number of endogenous and exogenous compounds. It has been estimated that 90% of human drug oxidation can be attributed to six main enzymes CYP 1A2, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1 and CYP 3A4/5 with the two most significant enzymes being CYP 3A4 and CYP 2D6. Recently, the cytochrome isoenzymes have been shown to be important in the synthesis of steroid hormones, bile acids, arachidonic acid and in CNS function. Cytochrome P450 enzymes can be inhibited or induced by drugs, resulting in clinically significant drug-drug interactions that can c...
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.
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.