CYP2C19

CYP2C19
Available structures PDB Human UniProt search: PDBe RCSB List of PDB id codes 4GQS
Identifiers
Aliases	CYP2C19, CPCJ, CYP2C, CYPIIC17, CYPIIC19, P450C2C, P450IIC19, cytochrome P450 family 2 subfamily C member 19
External IDs	HomoloGene: 133565 GeneCards: CYP2C19
EC number	1.14.13.48
Gene ontology Molecular function • iron ion binding • oxygen binding • (R)-limonene 6-monooxygenase activity • (S)-limonene 6-monooxygenase activity • (S)-limonene 7-monooxygenase activity • arachidonic acid epoxygenase activity • metal ion binding • monooxygenase activity • steroid hydroxylase activity • heme binding • oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen • enzyme binding • oxidoreductase activity Cellular component • organelle membrane • endoplasmic reticulum membrane • membrane • intracellular membrane-bounded organelle • endoplasmic reticulum Biological process • steroid metabolic process • exogenous drug catabolic process • epoxygenase P450 pathway • omega-hydroxylase P450 pathway • heterocycle metabolic process • drug metabolic process • monoterpenoid metabolic process • xenobiotic metabolic process • oxidation-reduction process Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1557	n/a
Ensembl	ENSG00000165841	n/a
UniProt	P33261	n/a
RefSeq (mRNA)	NM_000769	n/a
RefSeq (protein)	NP_000760.1	n/a
Location (UCSC)	Chr 10: 94.76 – 94.85 Mb	n/a
PubMed search	[1]	n/a
Wikidata

Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme. This protein, a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics, including many proton pump inhibitors and antiepileptics. In humans, the CYP2C19 protein is encoded by the CYP2C19 gene.^[2][3] CYP2C19 is a liver enzyme that acts on 10-15% of drugs in current clinical use,^[4] including the antiplatelet clopidogrel (Plavix), drugs that treat pain associated with ulcers, such as omeprazole, antiseizure drugs such as mephenytoin, the antimalarial proguanil, and the anxiolytic diazepam.^[5]

CYP2C19 has been annotated as (R)-limonene 6-monooxygenase and (S)-limonene 6-monooxygenase in UniProt.

Function

The gene encodes a member of the cytochrome P450 superfamily of enzymes. These proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and is known to metabolize many drugs. Polymorphism within this gene is associated with variable ability to metabolize mephenytoin, known as the poor metabolizer and extensive metabolizer phenotypes. The gene is located within a cluster of cytochrome P450 genes on chromosome no.10 arm q24.^[6]

CYP2C19 also possesses epoxygenase activitiy: it is one of the principal enzymes responsible for attacking various long-chain polyunsaturated fatty acids at their double (i.e. alkene) bonds to form epoxide products that act as signaling agents. It metabolizes:

1. arachidonic acid to various epoxyeicosatrienoic acids (also termed EETs);
2. linoleic acid to 9,10-epoxy octadecaenoic acids (also termed vernolic acid, linoleic acid 9:10-oxide, or leukotoxin) and 12,13-epoxy-octadecaenoic (also termed coronaric acid, linoleic acid 12,13-oxide, or isoleukotoxin);
3. docosohexaenoic acid to various epoxydocosapentaenoic acids (also termed EDPs); and
4. eicosapentaenoic acid to various epoxyeicosatetraenoic acids (also termed EEQs).^[7][8][9]

Along with CYP219, CYP2C8, CYP2C9, CYP2J2, and possibly CYP2S1 are the main producers of EETs and, very likely EEQs, EDPs, and the epoxides of linoleic acid.^[8][10]

Genetic polymorphism and pharmacogenomics

Genetic polymorphism (mainly CYP2C19*2, CYP2C19*3 and CYP2C19*17) exists for CYP2C19 expression, with approximately 3–5% of Caucasian and 15–20% of Asian populations being poor metabolizers with no CYP2C19 function.^[11][12] This may reduce the efficacy of clopidogrel (Plavix). In patients with an abnormal CYP2C19 variant certain benzodiazepines should be avoided, such as diazepam (Valium), lorazepam (Ativan), oxazepam (Serax), and temazepam (Restoril).^[13] On the basis of their ability to metabolize (S)-mephenytoin or other CYP2C19 substrates, individuals can be classified as extensive metabolizers (EM) or poor metabolizers (PM).^[12] Eight variant alleles (CYP2C19*2 to CYP2C19*8) that predict PMs have been identified.^[12]

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, 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.^[14]
• Moderate being one that causes at least a 2-fold increase in the plasma AUC values, or 50-80% decrease in clearance of substrates.^[14]
• 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.^[14]

See also

• Cytochrome P450 oxidase

References

Further reading

External links

• PharmGKB: Annotated PGx Gene Information for CYP2C19

PDB gallery
1r9o: Crystal Structure of P4502C9 with Flurbiprofen bound