-
International Journal of Molecular... Nov 2021Human cytochrome P450 (CYP) enzymes, as membrane-bound hemoproteins, play important roles in the detoxification of drugs, cellular metabolism, and homeostasis. In... (Review)
Review
Human cytochrome P450 (CYP) enzymes, as membrane-bound hemoproteins, play important roles in the detoxification of drugs, cellular metabolism, and homeostasis. In humans, almost 80% of oxidative metabolism and approximately 50% of the overall elimination of common clinical drugs can be attributed to one or more of the various CYPs, from the CYP families 1-3. In addition to the basic metabolic effects for elimination, CYPs are also capable of affecting drug responses by influencing drug action, safety, bioavailability, and drug resistance through metabolism, in both metabolic organs and local sites of action. Structures of CYPs have recently provided new insights into both understanding the mechanisms of drug metabolism and exploiting CYPs as drug targets. Genetic polymorphisms and epigenetic changes in CYP genes and environmental factors may be responsible for interethnic and interindividual variations in the therapeutic efficacy of drugs. In this review, we summarize and highlight the structural knowledge about CYPs and the major CYPs in drug metabolism. Additionally, genetic and epigenetic factors, as well as several intrinsic and extrinsic factors that contribute to interindividual variation in drug response are also reviewed, to reveal the multifarious and important roles of CYP-mediated metabolism and elimination in drug therapy.
Topics: Animals; Cytochrome P-450 Enzyme System; Humans; Inactivation, Metabolic; Metabolic Clearance Rate; Pharmaceutical Preparations; Polymorphism, Genetic; Xenobiotics
PubMed: 34884615
DOI: 10.3390/ijms222312808 -
The Journal of Biological Chemistry Feb 2019In honor of the 100th birthday of Dr. Herbert Tabor, JBC's Editor-in-Chief for 40 years, I will review here JBC's extensive coverage of the field of cytochrome P450... (Review)
Review
In honor of the 100th birthday of Dr. Herbert Tabor, JBC's Editor-in-Chief for 40 years, I will review here JBC's extensive coverage of the field of cytochrome P450 (P450) research. Research on the reactions catalyzed by these enzymes was published in JBC before it was even realized that they were P450s, they have a "pigment" with an absorption maximum at 450 nm. After the P450 pigment discovery, reported in JBC in 1962, the journal proceeded to publish the methods for measuring P450 activities and many seminal findings. Since then, the P450 field has grown extensively, with significant progress in characterizing these enzymes, including structural features, catalytic mechanisms, regulation, and many other aspects of P450 biochemistry. JBC has been the most influential journal in the P450 field. As with many other research areas, Dr. Tabor deserves a great deal of the credit for significantly advancing this burgeoning and important topic of research.
Topics: Biochemistry; Biomedical Research; Cytochrome P-450 Enzyme System; History, 20th Century; History, 21st Century; Humans
PubMed: 29871932
DOI: 10.1074/jbc.TM118.004144 -
The Journal of Biological Chemistry Jan 2020Cytochrome P450 enzymes (P450s) are broadly distributed among living organisms and play crucial roles in natural product biosynthesis, degradation of xenobiotics,... (Review)
Review
Cytochrome P450 enzymes (P450s) are broadly distributed among living organisms and play crucial roles in natural product biosynthesis, degradation of xenobiotics, steroid biosynthesis, and drug metabolism. P450s are considered as the most versatile biocatalysts in nature because of the vast variety of substrate structures and the types of reactions they catalyze. In particular, P450s can catalyze regio- and stereoselective oxidations of nonactivated C-H bonds in complex organic molecules under mild conditions, making P450s useful biocatalysts in the production of commodity pharmaceuticals, fine or bulk chemicals, bioremediation agents, flavors, and fragrances. Major efforts have been made in engineering improved P450 systems that overcome the inherent limitations of the native enzymes. In this review, we focus on recent progress of different strategies, including protein engineering, redox-partner engineering, substrate engineering, electron source engineering, and P450-mediated metabolic engineering, in efforts to more efficiently produce pharmaceuticals and other chemicals. We also discuss future opportunities for engineering and applications of the P450 systems.
Topics: Biocatalysis; Biotechnology; Cytochrome P-450 Enzyme System; Metabolic Engineering; Protein Engineering; Steroids; Substrate Specificity; Xenobiotics
PubMed: 31811088
DOI: 10.1074/jbc.REV119.008758 -
Pharmacology & Therapeutics Apr 2013Cytochromes P450 (CYP) are a major source of variability in drug pharmacokinetics and response. Of 57 putatively functional human CYPs only about a dozen enzymes,... (Review)
Review
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.
Topics: Animals; Cytochrome P-450 Enzyme System; Gene Expression Regulation, Enzymologic; Genetic Variation; Humans; NADPH-Ferrihemoprotein Reductase
PubMed: 23333322
DOI: 10.1016/j.pharmthera.2012.12.007 -
Trends in Pharmacological Sciences Aug 2016Cytochrome P450 (P450) enzymes are important in the metabolism of drugs, steroids, fat-soluble vitamins, carcinogens, pesticides, and many other types of chemicals.... (Review)
Review
Cytochrome P450 (P450) enzymes are important in the metabolism of drugs, steroids, fat-soluble vitamins, carcinogens, pesticides, and many other types of chemicals. Their catalytic activities are important issues in areas such as drug-drug interactions and endocrine function. During the past 30 years, structures of P450s have been very helpful in understanding function, particularly the mammalian P450 structures available in the past 15 years. We review recent activity in this area, focusing on the past 2 years (2014-2015). Structural work with microbial P450s includes studies related to the biosynthesis of natural products and the use of parasitic and fungal P450 structures as targets for drug discovery. Studies on mammalian P450s include the utilization of information about 'drug-metabolizing' P450s to improve drug development and also to understand the molecular bases of endocrine dysfunction.
Topics: Cytochrome P-450 Enzyme System; Humans; Models, Molecular; Pharmaceutical Preparations; Pharmacokinetics; Structure-Activity Relationship
PubMed: 27267697
DOI: 10.1016/j.tips.2016.05.006 -
American Family Physician Aug 2007Cytochrome P450 enzymes are essential for the metabolism of many medications. Although this class has more than 50 enzymes, six of them metabolize 90 percent of drugs,... (Review)
Review
Cytochrome P450 enzymes are essential for the metabolism of many medications. Although this class has more than 50 enzymes, six of them metabolize 90 percent of drugs, with the two most significant enzymes being CYP3A4 and CYP2D6. Genetic variability (polymorphism) in these enzymes may influence a patient's response to commonly prescribed drug classes, including beta blockers and antidepressants. Cytochrome P450 enzymes can be inhibited or induced by drugs, resulting in clinically significant drug-drug interactions that can cause unanticipated adverse reactions or therapeutic failures. Interactions with warfarin, antidepressants, antiepileptic drugs, and statins often involve the cytochrome P450 enzymes. Knowledge of the most important drugs metabolized by cytochrome P450 enzymes, as well as the most potent inhibiting and inducing drugs, can help minimize the possibility of adverse drug reactions and interactions. Although genotype tests can determine if a patient has a specific enzyme polymorphism, it has not been determined if routine use of these tests will improve outcomes.
Topics: Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Genotype; Humans; Pharmaceutical Preparations; Pharmacogenetics; Polymorphism, Genetic
PubMed: 17708140
DOI: No ID Found -
International Journal of Molecular... Jan 2023The mammalian cytochrome P450 monooxygenase CYP4B1 can bioactivate a wide range of xenobiotics, such as its defining/hallmark substrate 4-ipomeanol leading to... (Review)
Review
The mammalian cytochrome P450 monooxygenase CYP4B1 can bioactivate a wide range of xenobiotics, such as its defining/hallmark substrate 4-ipomeanol leading to tissue-specific toxicities. Similar to other members of the CYP4 family, CYP4B1 has the ability to hydroxylate fatty acids and fatty alcohols. Structural insights into the enigmatic role of CYP4B1 with functions in both, xenobiotic and endobiotic metabolism, as well as its unusual heme-binding characteristics are now possible by the recently solved crystal structures of native rabbit CYP4B1 and the p.E310A variant. Importantly, CYP4B1 does not play a major role in hepatic P450-catalyzed phase I drug metabolism due to its predominant extra-hepatic expression, mainly in the lung. In addition, no catalytic activity of human CYP4B1 has been observed owing to a unique substitution of an evolutionary strongly conserved proline 427 to serine. Nevertheless, association of CYP4B1 expression patterns with various cancers and potential roles in cancer development have been reported for the human enzyme. This review will summarize the current status of CYP4B1 research with a spotlight on its roles in the metabolism of endogenous and exogenous compounds, structural properties, and cancer association, as well as its potential application in suicide gene approaches for targeted cancer therapy.
Topics: Animals; Humans; Rabbits; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 Enzyme System; Fatty Acids; Mammals; Xenobiotics
PubMed: 36768362
DOI: 10.3390/ijms24032038 -
Molecules (Basel, Switzerland) Apr 2019Cytochrome P450 enzymes (CYPs) are important phase I enzymes involved in the metabolism of endogenous and xenobiotic compounds mainly through mono-oxygenation reactions... (Review)
Review
Cytochrome P450 enzymes (CYPs) are important phase I enzymes involved in the metabolism of endogenous and xenobiotic compounds mainly through mono-oxygenation reactions into more polar and easier to excrete species. In addition to their role in detoxification, they play important roles in the biosynthesis of endogenous compounds and the bioactivation of xenobiotics. Coumarins, phytochemicals abundant in food and commonly used in fragrances and cosmetics, have been shown to interact with P450 enzymes as substrates and/or inhibitors. In this review, these interactions and their significance in pharmacology and toxicology are discussed in detail.
Topics: Coumarins; Cytochrome P-450 Enzyme System; Humans; Metabolic Detoxication, Phase I; Models, Molecular; Quantitative Structure-Activity Relationship; Xenobiotics
PubMed: 31022888
DOI: 10.3390/molecules24081620 -
Pharmacology Research & Perspectives Feb 2023Scientific literature describes that sumatriptan is metabolized by oxidative deamination of its dimethylaminoethyl residue by monoamine oxidase A (MAO A) and not by...
Scientific literature describes that sumatriptan is metabolized by oxidative deamination of its dimethylaminoethyl residue by monoamine oxidase A (MAO A) and not by cytochrome P450 (CYP)-mediated demethylation, as is usual for such structural elements. Using recombinant human enzymes and HPLC-MS analysis, we found that CYP enzymes may also be involved in the metabolism of sumatriptan. The CYP1A2, CYP2C19, and CYP2D6 isoforms converted this drug into N-desmethyl sumatriptan, which was further demethylated to N,N-didesmethyl sumatriptan by CYP1A2 and CYP2D6. Otherwise, sumatriptan and its two desmethyl metabolites were metabolized by recombinant MAO A but not by MAO B to the corresponding acetaldehyde, with sumatriptan being only a poor substrate for MAO A compared to the N-demethylated and the N,N-didemethylated derivatives.
Topics: Humans; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2D6; Cytochrome P-450 Enzyme System; Microsomes, Liver; Monoamine Oxidase; Sumatriptan
PubMed: 36655303
DOI: 10.1002/prp2.1051 -
Drug Metabolism Reviews May 2019The oxidation of carbon-carbon triple bonds by cytochrome P450 produces ketene metabolites that are hydrolyzed to acetic acid derivatives or are trapped by nucleophiles.... (Review)
Review
The oxidation of carbon-carbon triple bonds by cytochrome P450 produces ketene metabolites that are hydrolyzed to acetic acid derivatives or are trapped by nucleophiles. In the special case of 17α-ethynyl sterols, D-ring expansion and de-ethynylation have been observed as competing pathways. The oxidation of acetylenic groups is also associated with mechanism-based inactivation of cytochrome P450 enzymes. One mechanism for this inactivation is reaction of the ketene metabolite with cytochrome P450 residues essential for substrate binding or catalysis. However, in the case of monosubstituted acetylenes, inactivation can also occur by addition of the oxidized acetylenic function to a nitrogen of the heme prosthetic group. This addition reaction is not mediated by the ketene metabolite, but rather occurs during oxygen transfer to the triple bond. In some instances, a detectable intermediate is formed that is most consistent with a ketocarbene-iron heme complex. This complex can progress to the N-alkylated heme or revert back to the unmodified enzyme. The ketocarbene complex may intervene in the formation of all the N-alkyl heme adducts, but is normally too unstable to be detected.
Topics: Alkynes; Animals; Cytochrome P-450 Enzyme System; Enzyme Activation; Humans; Oxidation-Reduction
PubMed: 31203694
DOI: 10.1080/03602532.2019.1632891