Cytochrome P450
Cytochrome P450 | |||||||||
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OPM superfamily | 39 | ||||||||
OPM protein | 2bdm | ||||||||
CDD | cd00302 | ||||||||
Membranome | 265 | ||||||||
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Cytochromes P450 (P450s or CYPs) are a superfamily of enzymes containing heme as a cofactor that mostly, but not exclusively, function as monooxygenases.[1][2][3] In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compounds, as well as for hormone synthesis and breakdown, steroid hormone synthesis, drug metabolism, and the biosynthesis of defensive compounds, fatty acids, and hormones.[2] CYP450 enzymes convert xenobiotics into hydrophilic derivatives, which are more readily excreted. In almost all of the transformations that they catalyze, P450's affect hydroxylation.
P450 enzymes have been identified in all kingdoms of life: animals, plants, fungi, protists, bacteria, and archaea, as well as in viruses.[4] However, they are not omnipresent; for example, they have not been found in Escherichia coli.[3][5] As of 2018[update], more than 300,000 distinct CYP proteins are known.[6][7]
P450s are, in general, the terminal oxidase enzymes in electron transfer chains, broadly categorized as P450-containing systems. The term "P450" is derived from the spectrophotometric peak at the wavelength of the absorption maximum of the enzyme (450 nm) when it is in the reduced state and complexed with carbon monoxide. Most P450s require a protein partner to deliver one or more electrons to reduce the iron (and eventually molecular oxygen).
Nomenclature
The current nomenclature guidelines suggest that members of new CYP families share at least 40% amino-acid identity, while members of subfamilies must share at least 55% amino-acid identity. Nomenclature committees assign and track both base gene names (Cytochrome P450 Homepage Archived 2010-06-27 at the Wayback Machine) and allele names (CYP Allele Nomenclature Committee).[9][10]
Classification
Based on the nature of the electron transfer proteins, P450s can be classified into several groups:[11]
- Microsomal P450 systems
- in which electrons are transferred from NADPH via cytochrome P450 reductase (variously CPR, POR, or CYPOR). Cytochrome b5 (cyb5) can also contribute reducing power to this system after being reduced by cytochrome b5 reductase (CYB5R).
- Mitochondrial P450 systems
- which employ adrenodoxinto transfer electrons from NADPH to P450.
- Bacterial P450 systems
- which employ a ferredoxin reductase and a ferredoxin to transfer electrons to P450.
- CYB5R/cyb5/P450 systems
- in which both electrons required by the CYP come from cytochrome b5.
- FMN/Fd/P450 systems
- originally found in reductaseis fused to the CYP.
- P450 only systems
- which do not require external reducing power. Notable ones include thromboxane synthase (CYP5), prostacyclin synthase (CYP8), and CYP74A (allene oxide synthase).
The most common reaction catalyzed by cytochromes P450 is a monooxygenase reaction, e.g., insertion of one atom of oxygen into the aliphatic position of an organic substrate (RH), while the other oxygen atom is reduced to water:
Many
Mechanism
Structure
The active site of cytochrome P450 contains a heme-iron center. The iron is tethered to the protein via a
Catalytic cycle
- Substrate binds in proximity to the heme group, on the side opposite to the axial thiolate. Substrate binding induces a change in the conformation of the active site, often displacing a water molecule from the distal axial coordination position of the heme iron,[13] and changing the state of the heme iron from low-spin to high-spin.[14]
- Substrate binding induces electron transfer from NAD(P)H via reductase.[15]
- Molecular oxygen binds to the resulting ferrous heme center at the distal axial coordination position, initially giving a dioxygen adduct similar to oxy-myoglobin.
- A second electron is transferred, from either cytochrome P450 reductase, ferredoxins, or cytochrome b5, reducing the Fe-O2 adduct to give a short-lived peroxo state.
- The peroxo group formed in step 4 is rapidly protonated twice, releasing one molecule of water and forming the highly reactive species referred to as P450 Compound 1 (or just Compound I). This highly reactive intermediate was isolated in 2010,delocalized over the porphyrin and thiolate ligands. Evidence for the alternative perferryl iron(V)-oxo[13] is lacking.[16]
- Depending on the substrate and enzyme involved, P450 enzymes can catalyze any of a wide variety of reactions. A hypothetical hydroxylation is shown in this illustration. After the product has been released from the active site, the enzyme returns to its original state, with a water molecule returning to occupy the distal coordination position of the iron nucleus.
- An alternative route for mono-oxygenation is via the "peroxide shunt" (path "S" in figure). This pathway entails oxidation of the ferric-substrate complex with oxygen-atom donors such as peroxides and hypochlorites.[17] A hypothetical peroxide "XOOH" is shown in the diagram.
Spectroscopy
Binding of substrate is reflected in the spectral properties of the enzyme, with an increase in absorbance at 390 nm and a decrease at 420 nm. This can be measured by difference spectroscopies and is referred to as the "type I" difference spectrum (see inset graph in figure). Some substrates cause an opposite change in spectral properties, a "reverse type I" spectrum, by processes that are as yet unclear. Inhibitors and certain substrates that bind directly to the heme iron give rise to the type II difference spectrum, with a maximum at 430 nm and a minimum at 390 nm (see inset graph in figure). If no reducing equivalents are available, this complex may remain stable, allowing the degree of binding to be determined from absorbance measurements in vitro[17] C: If carbon monoxide (CO) binds to reduced P450, the catalytic cycle is interrupted. This reaction yields the classic CO difference spectrum with a maximum at 450 nm. However, the interruptive and inhibitory effects of CO varies upon different CYPs such that the CYP3A family is relatively less affected.[18]
P450s in humans
Human P450s are primarily membrane-associated proteins.
The Human Genome Project has identified 57 human genes coding for the various cytochrome P450 enzymes.[20]
Drug metabolism
P450s are the major enzymes involved in
The CYP450 enzyme superfamily comprises 57 active subsets, with seven playing a crucial role in the metabolism of most pharmaceuticals.[23] The fluctuation in the amount of CYP450 enzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) in phase 1 (detoxification) can have varying effects on individuals, as genetic expression varies from person to person. This variation is due to the enzyme’s genetic polymorphism, which leads to variability in its function and expression. To optimize drug metabolism in individuals, genetic testing should be conducted to determine functional foods and specific phytonutrients that cater to the individual’s CYP450 polymorphism. Understanding these genetic variations can help personalize drug therapies for improved effectiveness and reduced adverse reactions.[24]
Drug interaction
Many drugs may increase or decrease the activity of various P450
Effects on P450 isozyme activity are a major source of adverse
Many substrates for CYP3A4 are drugs with a narrow
Interaction of other substances
Naturally occurring compounds may also induce or inhibit P450 activity. For example,
Other examples:
- Tobacco smoking induces CYP1A2 (example CYP1A2 substrates are clozapine, olanzapine, and fluvoxamine)[31]
- At relatively high concentrations, starfruit juice has also been shown to inhibit CYP2A6 and other P450s.[32] Watercress is also a known inhibitor of the cytochrome P450 CYP2E1, which may result in altered drug metabolism for individuals on certain medications (e.g., chlorzoxazone).[33]
- Tributyltin has been found to inhibit the function of cytochrome P450, leading to masculinization of mollusks.[34]
- Goldenseal, with its two notable alkaloids berberine and hydrastine, has been shown to alter P450-marker enzymatic activities (involving CYP2C9, CYP2D6, and CYP3A4).[35]
Other specific P450 functions
Steroid hormones
A subset of cytochrome P450 enzymes play important roles in the synthesis of
, and peripheral tissue:- CYP11A1 (also known as P450scc or P450c11a1) in adrenal mitochondria affects "the activity formerly known as 20,22-desmolase" (steroid 20α-hydroxylase, steroid 22-hydroxylase, cholesterol side-chainscission).
- 18-hydroxylase, and steroid 18-methyloxidase activities.
- CYP11B2 (encoding the protein P450c11AS), found only in the mitochondria of the adrenal zona glomerulosa, has steroid 11β-hydroxylase, steroid 18-hydroxylase, and steroid 18-methyloxidase activities.
- CYP17A1, in endoplasmic reticulum of adrenal cortex has steroid 17α-hydroxylase and 17,20-lyase activities.
- 21-hydroxylaseactivity.
- estrogens.
Polyunsaturated fatty acids and eicosanoids
Certain cytochrome P450 enzymes are critical in metabolizing
- CYP1A1, CYP1A2, and CYP2E1 metabolize endogenous PUFAs to signaling molecules: they metabolize arachidonic acid (i.e. AA) to 19-hydroxyeicosatetraenoic acid (i.e. 19-HETE; see 20-hydroxyeicosatetraenoic acid); eicosapentaenoic acid (i.e. EPA) to epoxyeicosatetraenoic acids (i.e. EEQs); and docosahexaenoic acid (i.e. DHA) to epoxydocosapentaenoic acids (i.e. EDPs).
- CYP2C8, CYP2C9, CYP2C18, CYP2C19, and CYP2J2 metabolize endogenous PUFAs to signaling molecules: they metabolize AA to epoxyeicosatetraenoic acids (i.e. EETs); EPA to EEQs; and DHA to EDPs.
- CYP2S1 metabolizes PUFA to signaling molecules: it metabolizes AA to EETs and EPA to EEQs.
- CYP3A4 metabolizes AA to EET signaling molecules.
- CYP4A11 metabolizes endogenous PUFAs to signaling molecules: it metabolizes AA to 20-HETE and EETs; it also hydroxylates DHA to 22-hydroxy-DHA (i.e. 12-HDHA).
- 12-hydroxyeicosatetraenoic acid (12-HETE) to 12,20-diHETE, EETs to 20-hydroxy-EETs, and lipoxinsto 20-hydroxy products.
- CYP4F8 and CYP4F12 metabolize PUFAs to signaling molecules: they metabolizes EPA to EEQs and DHA to EDPs. They also metabolize AA to 18-hydroxyeicosatetraenoic acid (18-HETE) and 19-HETE.
- CYP4F11 inactivates or reduces the activity of signaling molecules: it metabolizes LTB4 to 20-hydroxy-LTB4, (5-HETE) to 5,20-diHETE, (5-oxo-ETE) to 5-oxo,20-hydroxy-ETE, (12-HETE) to 12,20-diHETE, (15-HETE) to 15,20-diHETE, EETs to 20-hydroxy-EETs, and lipoxins to 20-hydroxy products.
- Congenital ichthyosiform erythrodema in humans.[37]
CYP families in humans
Humans have 57 genes and more than 59 pseudogenes divided among 18 families of cytochrome P450 genes and 43 subfamilies.[38] This is a summary of the genes and of the proteins they encode. See the homepage of the cytochrome P450 Nomenclature Committee for detailed information.[20]
Family | Function | Members | Genes | Pseudogenes |
CYP1 | drug and steroid (especially estrogen) metabolism, benzo[a]pyrene toxification (forming (+)-benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide) | 3 subfamilies, 3 genes, 1 pseudogene | CYP1A1, CYP1A2, CYP1B1 | CYP1D1P |
CYP2 | drug and steroid metabolism | 13 subfamilies, 16 genes, 16 pseudogenes | CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2R1, CYP2S1, CYP2U1, CYP2W1 | Too many to list |
CYP3 | drug and steroid (including testosterone) metabolism | 1 subfamily, 4 genes, 4 pseudogenes | CYP3A4, CYP3A5, CYP3A7, CYP3A43 | CYP3A51P, CYP3A52P, CYP3A54P, CYP3A137P |
CYP4 | arachidonic acid or fatty acid metabolism | 6 subfamilies, 12 genes, 10 pseudogenes | CYP4A11, CYP4A22, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4F22, CYP4V2, CYP4X1, CYP4Z1 | Too many to list |
CYP5 | thromboxane A2 synthase | 1 subfamily, 1 gene | CYP5A1 | |
CYP7 | bile acid biosynthesis 7-alpha hydroxylase of steroid nucleus | 2 subfamilies, 2 genes | CYP7A1, CYP7B1 |
|
CYP8 | varied | 2 subfamilies, 2 genes | CYP8A1 (prostacyclin synthase), CYP8B1 (bile acid biosynthesis) |
|
CYP11 | steroid biosynthesis | 2 subfamilies, 3 genes | CYP11B2 |
|
CYP17 | steroid biosynthesis, 17-alpha hydroxylase | 1 subfamily, 1 gene | CYP17A1 | |
CYP19 | steroid biosynthesis: aromatase synthesizes estrogen | 1 subfamily, 1 gene | CYP19A1 |
|
CYP20 | unknown function | 1 subfamily, 1 gene | CYP20A1 | |
CYP21 | steroid biosynthesis | 1 subfamilies, 1 gene, 1 pseudogene | CYP21A2 |
CYP21A1P |
CYP24 | vitamin D degradation | 1 subfamily, 1 gene | CYP24A1 | |
CYP26 |
retinoic acid hydroxylase | 3 subfamilies, 3 genes | CYP26A1, CYP26B1, CYP26C1 | |
CYP27 | varied | 3 subfamilies, 3 genes | CYP27B1 (vitamin D3 1-alpha hydroxylase, activates vitamin D3), CYP27C1 (vitamin A1 to A2) |
|
CYP39 | 7-alpha hydroxylation of 24-hydroxycholesterol | 1 subfamily, 1 gene | CYP39A1 | |
CYP46 | cholesterol 24-hydroxylase | 1 subfamily, 1 gene, 1 pseudogene | CYP46A1 |
CYP46A4P |
CYP51 | cholesterol biosynthesis | 1 subfamily, 1 gene, 3 pseudogenes | CYP51A1 (lanosterol 14-alpha demethylase) |
CYP51P1, CYP51P2, CYP51P3 |
P450s in other species
Animals
Other animals often have more P450 genes than humans do. Reported numbers range from 35 genes in the sponge
The classes of P450s most often investigated in non-human animals are those either involved in
P450s have been extensively examined in
CYPs have also been extensively studied in
Microbial
Microbial cytochromes P450 are often soluble enzymes and are involved in diverse metabolic processes. In bacteria the distribution of P450s is very variable with many bacteria having no identified P450s (e.g. E.coli). Some bacteria, predominantly actinomycetes, have numerous P450s (e.g.,
- Cytochrome P450 cam (CYP101A1) originally from Pseudomonas putida has been used as a model for many cytochromes P450 and was the first cytochrome P450 three-dimensional protein structure solved by X-ray crystallography. This enzyme is part of a camphor-hydroxylating catalytic cycle consisting of two electron transfer steps from putidaredoxin, a 2Fe-2S cluster-containing protein cofactor.
- Cytochrome P450 eryF (CYP107A1) originally from the actinomycete bacterium Saccharopolyspora erythraea is responsible for the biosynthesis of the antibiotic erythromycin by C6-hydroxylation of the macrolide 6-deoxyerythronolide B.
- long-chain fatty acids at the ω–1 through ω–3 positions. Unlike almost every other known CYP (except CYP505A1, cytochrome P450 foxy), it constitutes a natural fusion protein between the CYP domain and an electron donating cofactor. Thus, BM3 is potentially very useful in biotechnological applications.[51][52]
- Cytochrome P450 119 (thermophillic archea Sulfolobus solfataricus [53] has been used in a variety of mechanistic studies.[16]Because thermophillic enzymes evolved to function at high temperatures, they tend to function more slowly at room temperature (if at all) and are therefore excellent mechanistic models.
Fungi
The commonly used
Plants
Cytochromes P450 are involved in a variety of processes of plant growth, development, and defense. It is estimated that P450 genes make up approximately 1% of the plant genome.[55][56] These enzymes lead to various fatty acid conjugates, plant hormones, secondary metabolites, lignins, and a variety of defensive compounds.[57]
Cytochromes P450 play an important role in plant defense– involvement in phytoalexin biosynthesis, hormone metabolism, and biosynthesis of diverse secondary metabolites.[58] The expression of cytochrome p450 genes is regulated in response to environmental stresses indicative of a critical role in plant defense mechanisms.[59]
Phytoalexins have shown to be important in plant defense mechanisms as they are antimicrobial compounds produced by plants in response to plant pathogens. Phytoalexins are not pathogen-specific, but rather plant-specific; each plant has its own unique set of phytoalexins. However, they can still attack a wide range of different pathogens. Arabidopsis is a plant closely related to cabbage and mustard and produces the phytoalexin camalexin. Camalexin originates from tryptophan and its biosynthesis involves five cytochrome P450 enzymes. The five cytochrome P450 enzymes include CYP79B2, CYP79B3, CYP71A12, CYP71A13, and CYP71B15. The first step of camalexin biosynthesis produces indole-3-acetaldoxime (IAOx) from tryptophan and is catalyzed by either CYP79B2 or CYP79B3. IAOx is then immediately converted to indole-3-acetonitrile (IAN) and is controlled by either CYP71A13 or its homolog CYP71A12. The last two steps of the biosynthesis pathway of camalexin are catalyzed by CYP71B15. In these steps, indole-3-carboxylic acid (DHCA) is formed from cysteine-indole-3-acetonitrile (Cys(IAN)) followed by the biosynthesis of camalexin. There are some intermediate steps within the pathway that remain unclear, but it is well understood that cytochrome P450 is pivotal in camalexin biosynthesis and that this phytoalexin plays a major role in plant defense mechanisms.[60]
Cytochromes P450 are largely responsible for the synthesis of the jasmonic acid (JA), a common hormonal defenses against abiotic and biotic stresses for plant cells. For example, a P450, CYP74A is involved in the dehydration reaction to produce an insatiable allene oxide from hydroperoxide.[61] JA chemical reactions are critical in the presence of biotic stresses that can be caused by plant wounding, specifically shown in the plant, Arabidopsis. As a prohormone, jasmonic acid must be converted to the JA-isoleucine (JA-Ile) conjugate by JAR1 catalysation in order to be considered activated. Then, JA-Ile synthesis leads to the assembly of the co-receptor complex compo`sed of COI1 and several JAZ proteins. Under low JA-Ile conditions, the JAZ protein components act as transcriptional repressors to suppress downstream JA genes. However, under adequate JA-Ile conditions, the JAZ proteins are ubiquitinated and undergo degradation through the 26S proteasome, resulting in functional downstream effects. Furthermore, several CYP94s (CYP94C1 and CYP94B3) are related to JA-Ile turnover and show that JA-Ile oxidation status impacts plant signaling in a catabolic manner.[55] Cytochrome P450 hormonal regulation in response to extracellular and intracellular stresses is critical for proper plant defense response. This has been proven through thorough analysis of various CYP P450s in jasmonic acid and phytoalexin pathways.
Cytochrome P450 aromatic O-demethylase, which is made of two distinct promiscuous parts: a cytochrome P450 protein (GcoA) and three domain reductase, is significant for its ability to convert Lignin, the aromatic biopolymer common in plant cell walls, into renewable carbon chains in a catabolic set of reactions. In short, it is a facilitator of a critical step in Lignin conversion.
InterPro subfamilies
This section may require cleanup to meet Wikipedia's quality standards. The specific problem is: broken links; fragmented paragraph. (September 2016) |
InterPro subfamilies:
- Cytochrome P450, B-class InterPro: IPR002397
- Cytochrome P450, mitochondrial InterPro: IPR002399
- Cytochrome P450, E-class, group I InterPro: IPR002401
- Cytochrome P450, E-class, group II InterPro: IPR002402
- Cytochrome P450, E-class, group IV InterPro: IPR002403
- Aromatase
Clozapine, imipramine, paracetamol, phenacetin Heterocyclic aryl amines Inducible and CYP1A2 5-10% deficient oxidize uroporphyrinogen to uroporphyrin (CYP1A2) in heme metabolism, but they may have additional undiscovered endogenous substrates. are inducible by some polycyclic hydrocarbons, some of which are found in cigarette smoke and charred food.
These enzymes are of interest, because in assays, they can activate compounds to carcinogens. High levels of CYP1A2 have been linked to an increased risk of colon cancer. Since the 1A2 enzyme can be induced by cigarette smoking, this links smoking with colon cancer.[62]
See also
- Steroidogenic enzyme
- Cytochrome P450 oxidoreductase deficiency
- CYP11 family
- Cytochrome P450 engineering
References
- PMID 1486867.
- ^ a b "Cytochrome P450". InterPro.
- ^ PMID 12369887.
- PMID 19515774.
- ISBN 978-0-470-01672-5.
- PMID 28502748.
- PMID 19951895.
- ^ "NCBI sequence viewer". Retrieved 2007-11-19.
- PMID 19951895.
- PMID 20736090.
- ISBN 978-0-7623-0113-3.
- ^ [1] Archived 2019-10-18 at the Wayback Machine PROSITE consensus pattern for P450
- ^ S2CID 33927145.
- PMID 3656428.
- PMID 228675.
- ^ S2CID 206528205.
- ^ ISBN 978-0-306-48324-0.
- S2CID 233205099.
- PMID 21744854.
- ^ a b "P450 Table". 8 April 2021.
- ^ doctorfungus > Antifungal Drug Interactions Archived 2012-08-01 at archive.today Content Director: Russell E. Lewis, Pharm.D. Retrieved on Jan 23, 2010
- S2CID 17548932. (Metabolism in this context is the chemical modification or degradation of drugs.)
- PMID 24481193.
- PMID 26167297.
- PMID 21070748.
- ^ "Carbamazepine: Watch for Many Potential Drug Interactions". Pharmacy Times. Archived from the original on 2020-10-14. Retrieved 2019-11-07.
- S2CID 11525439.
- ^ Zeratsky K (2008-11-06). "Grapefruit juice: Can it cause drug interactions?". Ask a food & nutrition specialist. MayoClinic.com. Retrieved 2009-02-09.
- PMID 16271822.
- PMID 15070158.
- S2CID 5397510.
- PMID 18261370.
- S2CID 43863786.
- ^ Walmsley S. "Tributyltin pollution on a global scale. An overview of relevant and recent research: impacts and issues" (PDF). WWF UK. Archived from the original (PDF) on 2014-04-07. Retrieved 2014-05-01.
- S2CID 2967171.
- ISSN 2002-4436.
- PMID 25982146.
- ^ Nelson D (2003). Cytochromes P450 in humans. Retrieved May 9, 2005.
- PMID 23297357.
- PMID 17097629.
- PMID 20462619.
- PMID 21616088.
- S2CID 41480564.
- PMID 24248381.
- PMID 37555735.
- PMID 16581251.
- PMID 12692562.
- S2CID 35526991.
- PMID 22151149.
- PMID 25294646.
- PMID 3086309.
- PMID 17073779.
- S2CID 19579406.
- PMID 2091733.
- ^ PMID 22687470.
- PMID 20920462.
- PMID 14503006.
- ISSN 2095-3119.
- PMID 22215670.
- PMID 32466087.
- ^ "Canvas Login". login.canvas.uw.edu. Retrieved 2022-06-07.
- PMID 23033231.
Further reading
- Gelboin HV, Krausz K (March 2006). "Monoclonal antibodies and multifunctional cytochrome P450: drug metabolism as paradigm". Journal of Clinical Pharmacology. 46 (3): 353–372. S2CID 33325397.
- Gelboin HV, Krausz KW, Gonzalez FJ, Yang TJ (November 1999). "Inhibitory monoclonal antibodies to human cytochrome P450 enzymes: a new avenue for drug discovery". Trends in Pharmacological Sciences. 20 (11): 432–438. PMID 10542439.
- "Cytochrome P450 Mediated Drug and Carcinogen Metabolism using Monoclonal Antibodies". home.ccr.cancer.gov. Retrieved 2018-04-02.
- Krausz KW, Goldfarb I, Buters JT, Yang TJ, Gonzalez FJ, Gelboin HV (November 2001). "Monoclonal antibodies specific and inhibitory to human cytochromes P450 2C8, 2C9, and 2C19". Drug Metabolism and Disposition. 29 (11): 1410–1423. PMID 11602516.
- Gonzalez FJ, Gelboin HV (1994). "Role of human cytochromes P450 in the metabolic activation of chemical carcinogens and toxins". Drug Metabolism Reviews. 26 (1–2): 165–183. PMID 8082563.
- Estabrook RW (December 2003). "A passion for P450s (Remembrances of the early history of research on cytochrome P450)". Drug Metabolism and Disposition. 31 (12): 1461–1473. S2CID 43655270.
External links
- Degtyarenko K (2009-01-09). "Directory of P450-containing Systems". International Centre for Genetic Engineering and Biotechnology. Archived from the original on 2016-07-16. Retrieved 2009-02-10.
- Flockhart DA (2008-09-04). "Human Cytochrome P450 (CYP) Allele Nomenclature Committee". Karolinska Institutet. Retrieved 2009-02-10.
- Preissner S (2010). "Cytochrome P450 database". Nucleic Acids Research. Archived from the original on 2011-11-03. Retrieved 2011-08-02.
- Sigaroudi A, Vollbrecht H (2019). "pharmacokinetic interaction table". Sigaroudi & Vollbrecht.
- Sim SC (2007). "Cytochrome P450 drug interaction table". Indiana University-Purdue University Indianapolis. Retrieved 2009-02-10.