Cytochrome P450

Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that 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. In plants, these proteins are important for the biosynthesis of defensive compounds, fatty acids, and hormones.[2]

Cytochrome P450
Structure of lanosterol 14α-demethylase (CYP51)
Identifiers
Symbolp450
PfamPF00067
InterProIPR001128
PROSITEPDOC00081
SCOPe2cpp / SUPFAM
OPM superfamily39
OPM protein2bdm
Membranome265

CYP 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] More than 50,000 distinct CYP proteins are known.[6]

CYPs 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 CYPs require a protein partner to deliver one or more electrons to reduce the iron (and eventually molecular oxygen).

Nomenclature

Genes encoding CYP enzymes, and the enzymes themselves, are designated with the root symbol CYP for the superfamily, followed by a number indicating the gene family, a capital letter indicating the subfamily, and another numeral for the individual gene. The convention is to italicise the name when referring to the gene. For example, CYP2E1 is the gene that encodes the enzyme CYP2E1—one of the enzymes involved in paracetamol (acetaminophen) metabolism. The CYP nomenclature is the official naming convention, although occasionally CYP450 or CYP450 is used synonymously. However, some gene or enzyme names for CYPs may differ from this nomenclature, denoting the catalytic activity and the name of the compound used as substrate. Examples include CYP5A1, thromboxane A2 synthase, abbreviated to TBXAS1 (ThromBoXane A2 Synthase 1), and CYP51A1, lanosterol 14-α-demethylase, sometimes unofficially abbreviated to LDM according to its substrate (Lanosterol) and activity (DeMethylation).[7]

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. There are nomenclature committees that assign and track both base gene names (Cytochrome P450 Homepage) and allele names (CYP Allele Nomenclature Committee).[8][9][10]

Classification
Main article: P450-containing systems

Based on the nature of the electron transfer proteins, CYPs 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 adrenodoxin reductase and adrenodoxin to 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 Rhodococcus species, in which a FMN-domain-containing reductase is 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:

RH + O2 + NADPH + H+ → ROH + H2O + NADP+

Many hydroxylation reactions (insertion of hydroxyl groups) use CYP enzymes.

Mechanism
The "Fe(V) intermediate" at the bottom left is a simplification: it is an Fe(IV) with a radical heme ligand.

Structure

The active site of cytochrome P450 contains a heme-iron center. The iron is tethered to the protein via a cysteine thiolate ligand. This cysteine and several flanking residues are highly conserved in known CYPs and have the formal PROSITE signature consensus pattern [FW] - [SGNH] - x - [GD] - {F} - [RKHPT] - {P} - C - [LIVMFAP] - [GAD].[12] Because of the vast variety of reactions catalyzed by CYPs, the activities and properties of the many CYPs differ in many aspects. In general, the P450 catalytic cycle proceeds as follows:

Catalytic cycle
  1. 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]
  2. Substrate binding induces electron transfer from NAD(P)H via cytochrome P450 reductase or another associated reductase.[15]
  3. Molecular oxygen binds to the resulting ferrous heme center at the distal axial coordination position, initially giving a dioxygen adduct not unlike oxy-myoglobin.
  4. 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.
  5. 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,[16] P450 Compound 1 is an iron(IV) oxo (or ferryl) species with an additional oxidizing equivalent delocalized over the porphyrin and thiolate ligands. Evidence for the alternative perferryl iron(V)-oxo [13] is lacking.[16]
  6. 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.
Oxygen rebound mechanism utilized by cytochrome P450 for conversion of hydrocarbons to alcohols via the action of "compound I", an iron(IV) oxide bound to a heme radical cation.
  1. 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.

P450s in humans

Human CYPs are primarily membrane-associated proteins[18] located either in the inner membrane of mitochondria or in the endoplasmic reticulum of cells. CYPs metabolize thousands of endogenous and exogenous chemicals. Some CYPs metabolize only one (or a very few) substrates, such as CYP19 (aromatase), while others may metabolize multiple substrates. Both of these characteristics account for their central importance in medicine. Cytochrome P450 enzymes are present in most tissues of the body, and play important roles in hormone synthesis and breakdown (including estrogen and testosterone synthesis and metabolism), cholesterol synthesis, and vitamin D metabolism. Cytochrome P450 enzymes also function to metabolize potentially toxic compounds, including drugs and products of endogenous metabolism such as bilirubin, principally in the liver.

The Human Genome Project has identified 57 human genes coding for the various cytochrome P450 enzymes.[19]

Drug metabolism
Proportion of antifungal drugs metabolized by different families of CYPs.[20]
Further information: Drug metabolism

CYPs are the major enzymes involved in drug metabolism, accounting for about 75% of the total metabolism.[21] Most drugs undergo deactivation by CYPs, either directly or by facilitated excretion from the body. Also, many substances are bioactivated by CYPs to form their active compounds like the antiplatelet drug clopidogrel.

Drug interaction

Many drugs may increase or decrease the activity of various CYP isozymes either by inducing the biosynthesis of an isozyme (enzyme induction) or by directly inhibiting the activity of the CYP (enzyme inhibition). A classical example includes anti-epileptic drugs, such as Phenytoin, which induces CYP1A2, CYP2C9, CYP2C19, and CYP3A4.

Effects on CYP isozyme activity are a major source of adverse drug interactions, since changes in CYP enzyme activity may affect the metabolism and clearance of various drugs. For example, if one drug inhibits the CYP-mediated metabolism of another drug, the second drug may accumulate within the body to toxic levels. Hence, these drug interactions may necessitate dosage adjustments or choosing drugs that do not interact with the CYP system. Such drug interactions are especially important to consider when using drugs of vital importance to the patient, drugs with significant side-effects, or drugs with a narrow therapeutic index, but any drug may be subject to an altered plasma concentration due to altered drug metabolism.

Many substrates for CYP3A4 are drugs with a narrow therapeutic index, such as amiodarone[22] or carbamazepine.[23] Because these drugs are metabolized by CYP3A4, the mean plasma levels of these drugs may increase because of enzyme inhibition or decrease because of enzyme induction.

Interaction of other substances

Naturally occurring compounds may also induce or inhibit CYP activity. For example, bioactive compounds found in grapefruit juice and some other fruit juices, including bergamottin, dihydroxybergamottin, and paradicin-A, have been found to inhibit CYP3A4-mediated metabolism of certain medications, leading to increased bioavailability and, thus, the strong possibility of overdosing.[24] Because of this risk, avoiding grapefruit juice and fresh grapefruits entirely while on drugs is usually advised.[25]

Other examples:

Other specific CYP functions

Steroid hormones
Steroidogenesis, showing many of the enzyme activities that are performed by cytochrome P450 enzymes.[33] HSD: Hydroxysteroid dehydrogenase.

A subset of cytochrome P450 enzymes play important roles in the synthesis of steroid hormones (steroidogenesis) by the adrenals, gonads, and peripheral tissue:

Polyunsaturated fatty acids and eicosanoids

Certain cytochrome P450 enzymes are critical in metabolizing polyunsaturated fatty acids (PUFAs) to biologically active, intercellular cell signaling molecules (eicosanoids) and/or metabolize biologically active metabolites of the PUFA to less active or inactive products. These CYPs possess cytochrome P450 omega hydroxylase and/or epoxygenase enzyme activity.

  • 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 ad 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).
  • CYP4F2, CYP4F3A, and CYP4F3B (see CYP4F3 for latter two CYPs) metabolize PUFAs to signaling molecules: they metabolizes AA to 20-HETE. They also metabolize EPA to 19-hydroxyeicosapentaenoic acid (19-HEPE) and 20-hydroxyeicosapentaenoic acid (20-HEPE) as well as metabolize DHA to 22-HDA. They also inactivate or reduce the activity of signaling molecules: they metabolize leukotriene B4 (LTB4) to 20-hydroxy-LTB4, 5-hydroxyeicosatetraenoic acid (5-HETE) to 5,20-diHETE, 5-oxo-eicosatetraenoic acid (5-oxo-ETE) to 5-oxo,20-hydroxy-ETE, 12-hydroxyeicosatetraenoic acid (12-HETE) to 12,20-diHETE, EETs to 20-hydroxy-EETs, and lipoxins to 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, EETs to 20-hydroxy-EETs, and lipoxins to 20-hydroxy products.
  • CYP4F22 ω-hydroxylates extremely long "very long chain fatty acids", i.e. fatty acids that are 28 or more carbons long. The ω-hydroxylation of these special fatty acids is critical to creating and maintaining the skin's water barrier function; autosomal recessive inactivating mutations of CYP4F22 are associated with the Lamellar ichthyosis subtype of Congenital ichthyosiform erythrodema in humans.[34]

CYP families in humans

Humans have 57 genes and more than 59 pseudogenes divided among 18 families of cytochrome P450 genes and 43 subfamilies.[35] 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.[19]

FamilyFunctionMembersGenespseudogenes
CYP1drug and steroid (especially estrogen) metabolism, benzo[a]pyrene toxification (forming (+)-benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide)3 subfamilies, 3 genes, 1 pseudogeneCYP1A1, CYP1A2, CYP1B1CYP1D1P
CYP2drug and steroid metabolism13 subfamilies, 16 genes, 16 pseudogenesCYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2R1, CYP2S1, CYP2U1, CYP2W1Too many to list
CYP3drug and steroid (including testosterone) metabolism1 subfamily, 4 genes, 4 pseudogenesCYP3A4, CYP3A5, CYP3A7, CYP3A43CYP3A51P, CYP3A52P, CYP3A54P, CYP3A137P
CYP4arachidonic acid or fatty acid metabolism6 subfamilies, 12 genes, 10 pseudogenesCYP4A11, CYP4A22, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4F22, CYP4V2, CYP4X1, CYP4Z1Too many to list
CYP5thromboxane A2 synthase1 subfamily, 1 geneCYP5A1
CYP7bile acid biosynthesis 7-alpha hydroxylase of steroid nucleus2 subfamilies, 2 genesCYP7A1, CYP7B1
CYP8varied2 subfamilies, 2 genesCYP8A1 (prostacyclin synthase), CYP8B1 (bile acid biosynthesis)
CYP11steroid biosynthesis2 subfamilies, 3 genesCYP11A1, CYP11B1, CYP11B2
CYP17steroid biosynthesis, 17-alpha hydroxylase1 subfamily, 1 geneCYP17A1
CYP19steroid biosynthesis: aromatase synthesizes estrogen1 subfamily, 1 geneCYP19A1
CYP20unknown function1 subfamily, 1 geneCYP20A1
CYP21steroid biosynthesis1 subfamilies, 1 gene, 1 pseudogeneCYP21A2CYP21A1P
CYP24vitamin D degradation1 subfamily, 1 geneCYP24A1
CYP26retinoic acid hydroxylase3 subfamilies, 3 genesCYP26A1, CYP26B1, CYP26C1
CYP27varied3 subfamilies, 3 genesCYP27A1 (bile acid biosynthesis), CYP27B1 (vitamin D3 1-alpha hydroxylase, activates vitamin D3), CYP27C1 (unknown function)
CYP397-alpha hydroxylation of 24-hydroxycholesterol1 subfamily, 1 geneCYP39A1
CYP46cholesterol 24-hydroxylase1 subfamily, 1 gene, 1 pseudogeneCYP46A1CYP46A4P
CYP51cholesterol biosynthesis1 subfamily, 1 gene, 3 pseudogenesCYP51A1 (lanosterol 14-alpha demethylase)CYP51P1, CYP51P2, CYP51P3

P450s in other species

Animals

Many animals have as many or more CYP genes than humans do. Reported numbers range from 35 genes in the sponge Amphimedon queenslandica to 235 genes in the cephalochordate Branchiostoma floridae.[36] Mice have genes for 101 CYPs, and sea urchins have even more (perhaps as many as 120 genes).[37] Most CYP enzymes are presumed to have monooxygenase activity, as is the case for most mammalian CYPs that have been investigated (except for, e.g., CYP19 and CYP5). Gene and genome sequencing is far outpacing biochemical characterization of enzymatic function, though many genes with close homology to CYPs with known function have been found, giving clues to their functionality.

The classes of CYPs most often investigated in non-human animals are those either involved in development (e.g., retinoic acid or hormone metabolism) or involved in the metabolism of toxic compounds (such as heterocyclic amines or polyaromatic hydrocarbons). Often there are differences in gene regulation or enzyme function of CYPs in related animals that explain observed differences in susceptibility to toxic compounds (ex. canines' inability to metabolize xanthines such as caffeine). Some drugs undergo metabolism in both species via different enzymes, resulting in different metabolites, while other drugs are metabolized in one species but excreted unchanged in another species. For this reason, one species's reaction to a substance is not a reliable indication of the substance's effects in humans. A species of Sonoran Desert Drosophila that uses an upregulated expression of the CYP28A1 gene for detoxification of cacti rot is Drosophila mettleri. Flies of this species have adapted an upregulation of this gene due to exposure of high levels of alkaloids in host plants.

CYPs have been extensively examined in mice, rats, dogs, and less so in zebrafish, in order to facilitate use of these model organisms in drug discovery and toxicology. Recently CYPs have also been discovered in avian species, in particular turkeys, that may turn out to be a useful model for cancer research in humans.[38] CYP1A5 and CYP3A37 in turkeys were found to be very similar to the human CYP1A2 and CYP3A4 respectively, in terms of their kinetic properties as well as in the metabolism of aflatoxin B1.[39]

CYPs have also been heavily studied in insects, often to understand pesticide resistance. For example, CYP6G1 is linked to insecticide resistance in DDT-resistant Drosophila melanogaster[40] and CYP6M2 in the mosquito malaria vector Anopheles gambiae is capable of directly metabolizing pyrethroids.[41]

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.,[42][43]). Those so far identified are generally involved in either biotransformation of xenobiotic compounds (e.g. CYP105A1 from Streptomyces griseolus metabolizes sulfonylurea herbicides to less toxic derivatives,[44]) or are part of specialised metabolite biosynthetic pathways (e.g. CYP170B1 catalyses production of the sesquiterpenoid albaflavenone in Streptomyces albus,[45]). Although no P450 has yet been shown to be essential in a microbe, the CYP105 family is highly conserved with a representative in every streptomycete genome sequenced so far ([46]). Due to the solubility of bacterial P450 enzymes, they are generally regarded as easier to work with than the predominantly membrane bound eukaryotic P450s. This, combined with the remarkable chemistry they catalyse, has led to many studies using the heterologously expressed proteins in vitro. Few studies have investigated what P450s do in vivo, what the natural substrate(s) are and how P450s contribute to survival of the bacteria in the natural environment.Three examples that have contributed significantly to structural and mechanistic studies are listed here, but many different families exist.

  • 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.
  • Cytochrome P450 BM3 (CYP102A1) from the soil bacterium Bacillus megaterium catalyzes the NADPH-dependent hydroxylation of several 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.[47][48]
  • Cytochrome P450 119 (CYP119A1) isolated from the thermophillic archea Sulfolobus solfataricus [49] 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 azole class antifungal drugs work by inhibition of the fungal cytochrome P450 14α-demethylase. This interrupts the conversion of lanosterol to ergosterol, a component of the fungal cell membrane. (This is useful only because humans' P450 have a different sensitivity; this is how this class of antifungals work.)[50]

Significant research is ongoing into fungal P450s, as a number of fungi are pathogenic to humans (such as Candida yeast and Aspergillus) and to plants.

Cunninghamella elegans is a candidate for use as a model for mammalian drug metabolism.

Plants

Plant cytochrome P450s are involved in a wide range of biosynthetic reactions and target a diverse range of biomolecules. These reactions lead to various fatty acid conjugates, plant hormones, secondary metabolites, lignins, and a variety of defensive compounds.[51] Plant genome annotations suggest that cytochrome P450 genes make up as much as 1% of the plant genes. The number and diversity of P450 genes is responsible, in part, for the multitude of bioactive compounds.[52]

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.

P450s in biotechnology

The remarkable reactivity and substrate promiscuity of P450s have long attracted the attention of chemists.[53] Recent progress towards realizing the potential of using P450s towards difficult oxidations have included: (i) eliminating the need for natural co-factors by replacing them with inexpensive peroxide containing molecules,[54] (ii) exploring the compatibility of P450s with organic solvents,[55] and (iii) the use of small, non-chiral auxiliaries to predictably direct P450 oxidation.

InterPro subfamilies

InterPro subfamilies:

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.[56]

gollark: Secretly rewrite the core in Python.
gollark: If you do want to do the path thing anyway python and whatever support (ish) CGI and whatnot.
gollark: Yes, that is basically cool and good™?
gollark: Sometimes an apioformic entity does not want their filesystem layout to correspond to the URLs.
gollark: Idea: secretly rewrite the framework for increased sanity and hope nobody notices.

See also

References
  1. Gonzalez FJ, Gelboin HV (November 1992). "Human cytochromes P450: evolution and cDNA-directed expression". Environmental Health Perspectives. 98: 81–5. doi:10.1289/ehp.929881. PMC 1519618. PMID 1486867.
  2. "Cytochrome P450". InterPro.
  3. Danielson PB (December 2002). "The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans". Current Drug Metabolism. 3 (6): 561–97. doi:10.2174/1389200023337054. PMID 12369887.
  4. Lamb DC, Lei L, Warrilow AG, Lepesheva GI, Mullins JG, Waterman MR, Kelly SL (August 2009). "The first virally encoded cytochrome p450". Journal of Virology. 83 (16): 8266–9. doi:10.1128/JVI.00289-09. PMC 2715754. PMID 19515774.
  5. Sigel R, Sigel A, Sigel H (2007). The Ubiquitous Roles of Cytochrome P450 Proteins: Metal Ions in Life Sciences. New York: Wiley. ISBN 978-0-470-01672-5.
  6. Nelson D (2009). "Cytochrome P450 Homepage". Human Genomics. University of Tennessee. 4 (1): 59–65. doi:10.1186/1479-7364-4-1-59. PMC 3500189. PMID 19951895. Retrieved 2014-11-13.
  7. "NCBI sequence viewer". Retrieved 2007-11-19.
  8. Nelson, DR (October 2009). "The cytochrome p450 homepage". Human Genomics. 4 (1): 59–65. doi:10.1186/1479-7364-4-1-59. PMC 3500189. PMID 19951895.
  9. Nelson, David R. (January 2011). "Progress in tracing the evolutionary paths of cytochrome P450". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1814 (1): 14–18. doi:10.1016/j.bbapap.2010.08.008. PMID 20736090.
  10. Nelson, David R. (January 2018). "Cytochrome P450 diversity in the tree of life". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1866 (1): 141–154. doi:10.1016/j.bbapap.2017.05.003. PMC 5681887. PMID 28502748.
  11. Hanukoglu I (1996). "Electron transfer proteins of cytochrome P450 systems" (PDF). Adv. Mol. Cell Biol. Advances in Molecular and Cell Biology. 14: 29–55. doi:10.1016/S1569-2558(08)60339-2. ISBN 9780762301133.
  12. PROSITE consensus pattern for P450
  13. Meunier B, de Visser SP, Shaik S (September 2004). "Mechanism of oxidation reactions catalyzed by cytochrome p450 enzymes". Chemical Reviews. 104 (9): 3947–80. doi:10.1021/cr020443g. PMID 15352783. S2CID 33927145.
  14. Poulos TL, Finzel BC, Howard AJ (June 1987). "High-resolution crystal structure of cytochrome P450cam". Journal of Molecular Biology. 195 (3): 687–700. doi:10.1016/0022-2836(87)90190-2. PMID 3656428.
  15. Sligar SG, Cinti DL, Gibson GG, Schenkman JB (October 1979). "Spin state control of the hepatic cytochrome P450 redox potential". Biochemical and Biophysical Research Communications. 90 (3): 925–32. doi:10.1016/0006-291X(79)91916-8. PMID 228675.
  16. Rittle J, Green MT (November 2010). "Cytochrome P450 compound I: capture, characterization, and C-H bond activation kinetics". Science. 330 (6006): 933–7. Bibcode:2010Sci...330..933R. doi:10.1126/science.1193478. PMID 21071661. S2CID 206528205.
  17. Ortiz de Montellano, Paul R.; Paul R. Ortiz de Montellano (2005). Cytochrome P450: structure, mechanism, and biochemistry (3rd ed.). New York: Kluwer Academic/Plenum Publishers. ISBN 978-0-306-48324-0.
  18. Berka K, Hendrychová T, Anzenbacher P, Otyepka M (October 2011). "Membrane position of ibuprofen agrees with suggested access path entrance to cytochrome P450 2C9 active site". The Journal of Physical Chemistry A. 115 (41): 11248–55. Bibcode:2011JPCA..11511248B. doi:10.1021/jp204488j. PMC 3257864. PMID 21744854.
  19. "P450 Table".
  20. doctorfungus > Antifungal Drug Interactions Archived 2012-08-01 at Archive.today Content Director: Russell E. Lewis, Pharm.D. Retrieved on Jan 23, 2010
  21. Guengerich FP (January 2008). "Cytochrome p450 and chemical toxicology". Chemical Research in Toxicology. 21 (1): 70–83. doi:10.1021/tx700079z. PMID 18052394. S2CID 17548932. (Metabolism in this context is the chemical modification or degradation of drugs.)
  22. Zahno, A; Brecht, K; Morand, R; Maseneni, S; Török, M; Lindinger, PW; Krähenbühl, S (1 February 2011). "The role of CYP3A4 in amiodarone-associated toxicity on HepG2 cells". Biochem Pharmacol. 81 (3): 432–41. doi:10.1016/j.bcp.2010.11.002. PMID 21070748.
  23. "Carbamazepine: Watch for Many Potential Drug Interactions". Pharmacy Times.
  24. Bailey DG, Dresser GK (2004). "Interactions between grapefruit juice and cardiovascular drugs". American Journal of Cardiovascular Drugs. 4 (5): 281–97. doi:10.2165/00129784-200404050-00002. PMID 15449971. S2CID 11525439.
  25. Zeratsky K (2008-11-06). "Grapefruit juice: Can it cause drug interactions?". Ask a food & nutrition specialist. MayoClinic.com. Retrieved 2009-02-09.
  26. Chaudhary A, Willett KL (January 2006). "Inhibition of human cytochrome CYP 1 enzymes by flavonoids of St. John's wort". Toxicology. 217 (2–3): 194–205. doi:10.1016/j.tox.2005.09.010. PMID 16271822.
  27. Strandell J, Neil A, Carlin G (February 2004). "An approach to the in vitro evaluation of potential for cytochrome P450 enzyme inhibition from herbals and other natural remedies". Phytomedicine. 11 (2–3): 98–104. doi:10.1078/0944-7113-00379. PMID 15070158.
  28. Kroon LA (September 2007). "Drug interactions with smoking". American Journal of Health-System Pharmacy. 64 (18): 1917–21. doi:10.2146/ajhp060414. PMID 17823102. S2CID 5397510.
  29. Zhang JW, Liu Y, Cheng J, Li W, Ma H, Liu HT, Sun J, Wang LM, He YQ, Wang Y, Wang ZT, Yang L (2007). "Inhibition of human liver cytochrome P450 by star fruit juice". Journal of Pharmacy & Pharmaceutical Sciences. 10 (4): 496–503. doi:10.18433/j30593. PMID 18261370.
  30. Leclercq I, Desager JP, Horsmans Y (August 1998). "Inhibition of chlorzoxazone metabolism, a clinical probe for CYP2E1, by a single ingestion of watercress". Clinical Pharmacology and Therapeutics. 64 (2): 144–9. doi:10.1016/S0009-9236(98)90147-3. PMID 9728894.
  31. Walmsley, Simon. "Tributyltin pollution on a global scale. An overview of relevant and recent research: impacts and issues" (PDF). WWF UK.
  32. Chatterjee P, Franklin MR (November 2003). "Human cytochrome p450 inhibition and metabolic-intermediate complex formation by goldenseal extract and its methylenedioxyphenyl components". Drug Metabolism and Disposition. 31 (11): 1391–7. doi:10.1124/dmd.31.11.1391. PMID 14570772. S2CID 2967171.
  33. Häggström, Mikael; Richfield, David (2014). "Diagram of the pathways of human steroidogenesis". WikiJournal of Medicine. 1 (1). doi:10.15347/wjm/2014.005. ISSN 2002-4436.
  34. Sugiura K, Akiyama M (July 2015). "Update on autosomal recessive congenital ichthyosis: mRNA analysis using hair samples is a powerful tool for genetic diagnosis". Journal of Dermatological Science. 79 (1): 4–9. doi:10.1016/j.jdermsci.2015.04.009. PMID 25982146.
  35. Nelson D (2003). Cytochromes P450 in humans. Retrieved May 9, 2005.
  36. Nelson DR, Goldstone JV, Stegeman JJ (February 2013). "The cytochrome P450 genesis locus: the origin and evolution of animal cytochrome P450s". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 368 (1612): 20120474. doi:10.1098/rstb.2012.0474. PMC 3538424. PMID 23297357.
  37. Goldstone JV, Hamdoun A, Cole BJ, Howard-Ashby M, Nebert DW, Scally M, Dean M, Epel D, Hahn ME, Stegeman JJ (December 2006). "The chemical defensome: environmental sensing and response genes in the Strongylocentrotus purpuratus genome". Developmental Biology. 300 (1): 366–84. doi:10.1016/j.ydbio.2006.08.066. PMC 3166225. PMID 17097629.
  38. Rawal S, Kim JE, Coulombe R (December 2010). "Aflatoxin B1 in poultry: toxicology, metabolism and prevention". Research in Veterinary Science. 89 (3): 325–31. doi:10.1016/j.rvsc.2010.04.011. PMID 20462619.
  39. Rawal S, Coulombe RA (August 2011). "Metabolism of aflatoxin B1 in turkey liver microsomes: the relative roles of cytochromes P450 1A5 and 3A37". Toxicology and Applied Pharmacology. 254 (3): 349–54. doi:10.1016/j.taap.2011.05.010. PMID 21616088.
  40. McCart C, Ffrench-Constant RH (June 2008). "Dissecting the insecticide-resistance- associated cytochrome P450 gene Cyp6g1". Pest Management Science. 64 (6): 639–45. doi:10.1002/ps.1567. PMID 18338338.
  41. Ismail, Hanafy; O'Neill, Paul; Hong, David; Finn, Robert; Henderson, Colin; Wright, Aaron; Cravatt, Benjamin; Hemingway, Janet; Paine, Mark (3 December 2013). "Pyrethroid activity-based probes for profiling cytochrome P450 activities associated with insecticide interactions". PNAS. 110 (49): 19766–19771. Bibcode:2013PNAS..11019766I. doi:10.1073/pnas.1320185110. PMC 3856776. PMID 24248381.
  42. McLean KJ, Clift D, Lewis DG, Sabri M, Balding PR, Sutcliffe MJ, Leys D, Munro AW (May 2006). "The preponderance of P450s in the Mycobacterium tuberculosis genome". Trends in Microbiology. 14 (5): 220–8. doi:10.1016/j.tim.2006.03.002. PMID 16581251.
  43. Ikeda H, Ishikawa J, Hanamoto A, Shinose M, Kikuchi H, Shiba T, Sakaki Y, Hattori M, Omura S (May 2003). "Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis". Nature Biotechnology. 21 (5): 526–31. doi:10.1038/nbt820. PMID 12692562.
  44. Leto, O'Keefe (1988). "Identification of constitutive and herbicide inducible cytochromes P-450 in Streptomyces griseolus". Arch Microbiol. 149 (5): 406–12. doi:10.1007/BF00425579. S2CID 35526991.
  45. Moody SC, Zhao B, Lei L, Nelson DR, Mullins JG, Waterman MR, Kelly SL, Lamb DC (May 2012). "Investigating conservation of the albaflavenone biosynthetic pathway and CYP170 bifunctionality in streptomycetes". The FEBS Journal. 279 (9): 1640–9. doi:10.1111/j.1742-4658.2011.08447.x. PMID 22151149.
  46. Moody SC, Loveridge EJ (December 2014). "CYP105-diverse structures, functions and roles in an intriguing family of enzymes in Streptomyces". Journal of Applied Microbiology. 117 (6): 1549–63. doi:10.1111/jam.12662. PMC 4265290. PMID 25294646.
  47. Narhi LO, Fulco AJ (June 1986). "Characterization of a catalytically self-sufficient 119,000-dalton cytochrome P-450 monooxygenase induced by barbiturates in Bacillus megaterium". The Journal of Biological Chemistry. 261 (16): 7160–9. PMID 3086309.
  48. Girvan HM, Waltham TN, Neeli R, Collins HF, McLean KJ, Scrutton NS, Leys D, Munro AW (December 2006). "Flavocytochrome P450 BM3 and the origin of CYP102 fusion species". Biochemical Society Transactions. 34 (Pt 6): 1173–7. doi:10.1042/BST0341173. PMID 17073779.
  49. Wright RL, Harris K, Solow B, White RH, Kennelly PJ (April 1996). "Cloning of a potential cytochrome P450 from the archaeon Sulfolobus solfataricus". FEBS Letters. 384 (3): 235–9. doi:10.1016/0014-5793(96)00322-5. PMID 8617361.
  50. Vanden Bossche H, Marichal P, Gorrens J, Coene MC (September 1990). "Biochemical basis for the activity and selectivity of oral antifungal drugs". British Journal of Clinical Practice. Supplement. 71: 41–6. PMID 2091733.
  51. Schuler MA, Werck-Reichhart D (2003-01-01). "Functional genomics of P450s". Annual Review of Plant Biology. 54 (1): 629–67. doi:10.1146/annurev.arplant.54.031902.134840. PMID 14503006.
  52. Mizutani M, Sato F (March 2011). "Unusual P450 reactions in plant secondary metabolism". Archives of Biochemistry and Biophysics. P450 Catalysis Mechanisms. 507 (1): 194–203. doi:10.1016/j.abb.2010.09.026. PMID 20920462.
  53. Chefson A, Auclair K (October 2006). "Progress towards the easier use of P450 enzymes". Molecular BioSystems. 2 (10): 462–9. doi:10.1039/b607001a. PMID 17216026.
  54. Chefson A, Zhao J, Auclair K (June 2006). "Replacement of natural cofactors by selected hydrogen peroxide donors or organic peroxides results in improved activity for CYP3A4 and CYP2D6". ChemBioChem. 7 (6): 916–9. doi:10.1002/cbic.200600006. PMID 16671126. S2CID 39329433.
  55. Chefson A, Auclair K (July 2007). "CYP3A4 activity in the presence of organic cosolvents, ionic liquids, or water-immiscible organic solvents". ChemBioChem. 8 (10): 1189–97. doi:10.1002/cbic.200700128. PMID 17526062.
  56. Petros WP, Younis IR, Ford JN, Weed SA (October 2012). "Effects of tobacco smoking and nicotine on cancer treatment". Pharmacotherapy. 32 (10): 920–31. doi:10.1002/j.1875-9114.2012.01117. PMC 3499669. PMID 23033231.

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