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Cytochrome P450 2C19 (abbreviated CYP2C19) is an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
protein. It is a member of the CYP2C subfamily of the
cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...
mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of
xenobiotic A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compo ...
s, including some proton pump inhibitors and
antiepileptic Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of b ...
drugs. In humans, it is the ''CYP2C19''
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
that encodes the CYP2C19 protein. CYP2C19 is a liver enzyme that acts on at least 10% of drugs in current clinical use, most notably the antiplatelet treatment
clopidogrel Clopidogrel — sold under the brand name Plavix, among others — is an antiplatelet medication used to reduce the risk of heart disease and stroke in those at high risk. It is also used together with aspirin in heart attacks and following ...
(Plavix), drugs that treat pain associated with ulcers, such as omeprazole, antiseizure drugs such as mephenytoin, the antimalarial
proguanil Proguanil, also known as chlorguanide and chloroguanide, is a medication used to treat and prevent malaria. It is often used together with chloroquine or atovaquone. When used with chloroquine the combination will treat mild chloroquine resista ...
, and the
anxiolytic An anxiolytic (; also antipanic or antianxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiet ...
diazepam Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, ...
. CYP2C19 has been annotated as (R)-limonene 6-monooxygenase and (S)-limonene 6-monooxygenase in
UniProt UniProt is a freely accessible database of protein sequence and functional information, many entries being derived from genome sequencing projects. It contains a large amount of information about the biological function of proteins derived from ...
.


Function

The gene encodes a member of the cytochrome P450 superfamily of enzymes. Enzymes in the CYP2C subfamily, including CYP2C19, account for approximately 20% of cytochrome P450 in the adult liver. These proteins are
monooxygenase Monooxygenases are enzymes that incorporate one hydroxyl group (−OH) into substrates in many metabolic pathways. In this reaction, the two atoms of dioxygen are reduced to one hydroxyl group and one H2O molecule by the concomitant oxidation o ...
s that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ...
and is known to metabolize many drugs. Polymorphism within this gene is associated with variable ability to metabolize drugs. The gene is located within a cluster of cytochrome P450 genes on chromosome no.10 arm q24. CYP2C19 also possesses
epoxygenase Epoxygenases are a set of membrane-bound, heme-containing cytochrome P450 (CYP P450 or just CYP) enzymes that metabolize polyunsaturated fatty acids to epoxide products that have a range of biological activities. The most thoroughly studied subs ...
activity: it is one of the principal enzymes responsible for attacking various long-chain polyunsaturated fatty acids at their double (i.e.
alkene In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond. Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic ...
) bonds to form
epoxide In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale ...
products that act as signaling agents. It metabolizes: #
arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''ara ...
to various
epoxyeicosatrienoic acid The epoxyeicosatrienoic acids or EETs are signaling molecules formed within various types of cells by the metabolism of arachidonic acid by a specific subset of Cytochrome P450 enzymes termed cytochrome P450 epoxygenases. These nonclassic eicos ...
s (also termed EETs); #
linoleic acid Linoleic acid (LA) is an organic compound with the formula COOH(CH2)7CH=CHCH2CH=CH(CH2)4CH3. Both alkene groups are ''cis''. It is a fatty acid sometimes denoted 18:2 (n-6) or 18:2 ''cis''-9,12. A linoleate is a salt or ester of this acid. ...
to 9,10-epoxy octadecaenoic acids (also termed
vernolic acid Vernolic acid (leukotoxin) is a long chain fatty acid that is monounsaturated and contains an epoxide. It is the R,R-''cis'' epoxide derived from the C12–C13 alkene of linoleic acid. Vernolic acid was first definitively characterized in 1954. ...
, linoleic acid 9:10-oxide, or leukotoxin) and 12,13-epoxy-octadecaenoic (also termed coronaric acid, linoleic acid 12,13-oxide, or isoleukotoxin); #
docosahexaenoic acid Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human brain, cerebral cortex, skin, and retina. In physiological literature, it is given the name 22:6(n-3). It can be synthesized from alpha-lin ...
to various
epoxydocosapentaenoic acid Epoxide docosapentaenoic acids (epoxydocosapentaenoic acids, EDPs, or EpDPEs) are metabolites of the 22-carbon straight-chain omega-3 fatty acid, docosahexaenoic acid (DHA). Cell types that express certain cytochrome P450 (CYP) epoxygenases met ...
s (also termed EDPs); and # eicosapentaenoic acid to various epoxyeicosatetraenoic acids (also termed EEQs). Along with CYP2C19,
CYP2C8 Cytochrome P4502C8 (abbreviated CYP2C8), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. Cytochrome P4502C8 also possesses epoxygenase activity, i.e. it metabolizes long-cha ...
,
CYP2C9 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the pro ...
,
CYP2J2 Cytochrome P450 2J2 (CYP2J2) is a protein that in humans is encoded by the ''CYP2J2'' gene. CYP2J2 is a member of the cytochrome P450 superfamily of enzymes. The enzymes are oxygenases which catalyze many reactions involved in the metabolism of ...
, and possibly CYP2S1 are the main producers of EETs and, very likely EEQs, EDPs, and the epoxides of linoleic acid.


Pharmacogenomics

Pharmacogenomics is a study that analyzes how an individual's genetic makeup affects the response to drugs of this individual. There are many common genetic variations that affect the expression of the ''CYP2C19 gene'', which in turn influence the enzyme activity in the metabolic pathways of those drugs in which this enzyme is involved. The Pharmacogene Variation Consortium keeps th
Human CYP Allele Nomenclature Database
and assigns labels to known polymorphisms that affect drug response. A label consists of an asterisk (*) character followed by a number. The most common variant (also called wild type) has CYP2C19*1 label. The variant genotypes of CYP2C19*2 (NM_000769.2:c.681GA; p.Pro227Pro; rs4244285), CYP2C19*3 (NM_000769.2:c.636G>A; p.Trp212Ter; rs4986893) and CYP2C19*17 (NM_000769.2:c.-806C>T; rs12248560) are major factors attributed to interindividual differences in the pharmacokinetics and response to CYP2C19 substrates. CYP2C19*2 and *3 ( loss-of-function alleles) are associated with diminished enzyme activity, whereas CYP2C19*17 ( gain-of-function allele) results in increased activity. The Working Group of the Association for Molecular Pathology Clinical Practice Committee recommended these three variant alleles to be included in the minimal clinical pharmacogenomic testing panel, called ''tier 1''. The extended panel of variant alleles, called ''tier 2'', additionally includes the following CYP2C19 alleles: *4.001 (*4A), *4.002 (*4B), *5, *6, *7, *8, *9, *10, and *35, all of them associated with diminished enzyme activity. Although these tier 2 alleles are included in many platforms, they were not included in the tier 1 recommendations because of low minor allele frequency (which can increase false-positive occurrences), less well-characterized impact on CYP2C19 function, or a lack of reference materials. In partnership with the clinical testing community, the Centers for Disease Control and Prevention established the Genetic Testing Reference Material Program to meet the need for publicly available characterized reference materials. Its goal is to improve the supply of publicly available and well-characterized genomic DNA used as reference materials for proficiency testing, quality control, test development/validation, and research studies. The allele frequencies of CYP2C19*2 and *3 are significantly higher in Chinese populations than in European or African populations, and are found at approximately 3–5% of European and 15–20% of Asian populations. Among Arab population, the frequency of CYP2C19 genotypes including *1/*17, *1/*2, *2/*2, *3/*3, and *1/*3 were 20.2%, 16.7%, 6.1%, 5.45%, 0.7%, and 0.35%, respectively. In a study of 2.29 million direct-to-consumer genetics research participants, the overall frequencies of *2, *3, and *17 were 15.2%, 0.3%, and 20.4%, respectively, but varied by ethnicity. The most common variant diplotypes were *1/*17 at 26% and *1/*2 at 19.4%. The less common *2/*17, *17/*17 and *2/*2 genotypes occurred at 6.0%, 4.4%, and 2.5%, respectively. Overall, 58.3% of participants had at least one increased-function or no-function CYP2C19 allele. CYP2C19 is involved in processing or metabolizing at least 10% of commonly prescribed drugs. Variations to the enzyme can have a wide range of impacts to drug metabolism. In patients with an abnormal CYP2C19 variant certain
benzodiazepine Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
s should be avoided, such as diazepam (Valium),
lorazepam Lorazepam, sold under the brand name Ativan among others, is a benzodiazepine medication. It is used to treat anxiety disorders, trouble sleeping, severe agitation, active seizures including status epilepticus, alcohol withdrawal, and che ...
(Ativan), oxazepam (Serax), and
temazepam Temazepam (sold under the brand names Restoril among others) is a medication of the benzodiazepine class which is generally used to treat severe or debilitating insomnia. It is taken by mouth. Temazepam is rapidly absorbed, and significant hyp ...
(Restoril). Other categories of drugs impacted by modified CYP2C19 include proton pump inhibitors, anticonvulsants, hypnotics, sedatives, antimalarial drugs, and antiretroviral drugs. On the basis of their ability to metabolize (S)-mephenytoin or other CYP2C19 substrates, individuals can be classified as ultrarapid metabolizers (UM), extensive metabolizers (EM) or poor metabolizers (PM). In the case of proton pump inhibitors, PMs exhibit a drug exposure that is 3 to 13 times higher than that of EMs. Loss-of-function alleles, CYP2C19*2 and CYP2C19*3 (and other, which are the subject of ongoing research) predict PMs, and the gain-of-function CYP2C19*17 allele predicts UMs. Although the amount of CYP2C19 enzyme produced by the *17 allele is greater than of the *1 allele, whether the carriers of the *17 allele experience any significant difference in response to drugs comparing to the wild-type, is a topic of ongoing research, studies show varying results. Some studies have found that the *17 variant's effect on the metabolism of omeprazole,
pantoprazole Pantoprazole, sold under the brand name Protonix, among others, is a proton pump inhibitor used for the treatment of stomach ulcers, short-term treatment of erosive esophagitis due to gastroesophageal reflux disease (GERD), maintenance of heal ...
, escitalopram,
sertraline Sertraline, sold under the brand name Zoloft among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. The efficacy of sertraline for depression is similar to that of other antidepressants, and the diffe ...
,
voriconazole Voriconazole, sold under the brand name Vfend among others, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, candidiasis, coccidioidomycosis, histoplasmosis, penicilliosis, and infections by ' ...
,
tamoxifen Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men. It is also being studied for other types of cancer. It has b ...
and
clopidogrel Clopidogrel — sold under the brand name Plavix, among others — is an antiplatelet medication used to reduce the risk of heart disease and stroke in those at high risk. It is also used together with aspirin in heart attacks and following ...
is modest, particularly compared to the impact of loss-of-function alleles (*2, *3), therefore, in case of these medications, the EM designation is sometimes applied instead of the UM one. For example, carriers of the *17 allele did not demonstrate different gastric pH comparing to *1 after taking the proton pump inhibitor omeprazole, a CYP2C19 substrate. Other studies concluded that the *17 allele seems to be the factor responsible for lower response to some drugs, even at higher doses, for example, to escitalopram for symptom remission in major depressive disorder patients. CYP2C19*17 carrier status is significantly associated with enhanced response to clopidogrel and an increased risk of bleeding; the highest risk was observed for CYP2C19*17 homozygous patients. A study found that escitalopram serum concentration was 42% lower in patients homozygous for CYP2C19*17. An important limitation of all these studies is the single-gene analysis, since most drugs that are metabolized by CYP2C19 are also metabolized by
CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2D ...
and
CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules ( xenobiotics), such as toxins or drugs, so that they can be removed from ...
enzymes. Besides that, other genes are involved in drug response, for example, escitalopram is transported by
P-glycoprotein P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...
, encoded by the '' ABCB1'' gene. In order for the studies on CYP2C19*17 to be conclusive, the differences in other genes that affect drug response have to be excluded. The prevalence of the CYP2C19*17 variant is less than 5% in Asian populations and is approximately four times higher in European and African populations. The alleles CYP2C19*2 and *3 may reduce the efficacy of clopidogrel (Plavix), an antiplatelet medication. The basis for this reduced effect of clopidogrel in patients who have a gene of reduced activity may seem somewhat paradoxical, but can be understood as follows. Clopidogrel is administered as a "prodrug", a drug that is inactive when taken, and then depends on the action of an enzyme in the body to be activated. In patients with a gene of reduced activity, clopidogrel may not be metabolized to its biologically active form and therefore not achieve pharmacological effect in the body. The relative risk of major cardiac events among patients treated with clopidogrel is 1.53 to 3.69 times higher for carriers of CYP2C19*2 and CYP2C19*3 compared with non-carriers. A 2020 systematic review and meta-analysis also confirmed that the CYP2C19*2 variant has a strong association with clopidogrel resistance. In 2021 a higher risk of stroke at 90 days was found with clopidogrel than
ticagrelor Ticagrelor, sold under the brand name Brilinta among others, is a medication used for the prevention of stroke, heart attack and other events in people with acute coronary syndrome, meaning problems with blood supply in the coronary arteries. It ...
, which does not require metabolic conversion, among Han Chinese CYP2C19 loss-of-function carriers with minor ischemic stroke or TIA.


Ligands

The following is a table of selected substrates, inducers and inhibitors of CYP2C19. Where classes of agents are listed, there may be exceptions within the class. Inhibitors of CYP2C19 can be classified by their
potency Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of how ...
, such as: *Strong being one that causes at least a 5-fold increase in the plasma AUC values, or more than 80% decrease in clearance of substrates. *Moderate being one that causes at least a 2-fold increase in the plasma AUC values, or 50–80% decrease in clearance of substrates. *Weak being one that causes at least a 1.25-fold but less than 2-fold increase in the plasma AUC values, or 20–50% decrease in clearance of substrates.


See also

* Cytochrome P450 oxidase


References


External links


PharmGKB: Annotated PGx Gene Information for CYP2C19
* {{DEFAULTSORT:Cyp2c19 2