Cytochrome P450, family 1, member A1

CYP1A1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4I8V
Identifiers
Aliases	CYP1A1, AHH, AHRR, CP11, CYP1, P1-450, P450-C, P450DX, CYPIA1, cytochrome P450 family 1 subfamily A member 1
External IDs	OMIM: 108330 MGI: 88588 HomoloGene: 68062 GeneCards: CYP1A1
Targeted by Drug
chrysin[1]
Gene ontology Molecular function • iron ion binding • oxygen binding • flavonoid 3'-monooxygenase activity • demethylase activity • oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen • metal ion binding • steroid hydroxylase activity • catalytic activity • protein binding • heme binding • oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen • enzyme binding • vitamin D 24-hydroxylase activity • oxidoreductase activity • aromatase activity • oxidoreductase activity, acting on diphenols and related substances as donors • monooxygenase activity Cellular component • cytoplasm • organelle membrane • endoplasmic reticulum membrane • intracellular membrane-bounded organelle • membrane • endoplasmic reticulum • mitochondrion Biological process • response to immobilization stress • toxin metabolic process • maternal process involved in parturition • response to hypoxia • 9-cis-retinoic acid biosynthetic process • response to organic cyclic compound • coumarin metabolic process • vitamin D metabolic process • insecticide metabolic process • response to hyperoxia • response to antibiotic • demethylation • cellular response to organic cyclic compound • response to virus • aging • hepatocyte differentiation • epoxygenase P450 pathway • dibenzo-p-dioxin catabolic process • developmental process • response to arsenic-containing substance • response to organic substance • embryo development ending in birth or egg hatching • positive regulation of G1/S transition of mitotic cell cycle • response to vitamin A • amine metabolic process • response to lipopolysaccharide • omega-hydroxylase P450 pathway • response to wounding • heterocycle metabolic process • dibenzo-p-dioxin metabolic process • response to nematode • response to iron(III) ion • flavonoid metabolic process • response to food • drug metabolic process • hydrogen peroxide biosynthetic process • liver development • camera-type eye development • digestive tract development • cell proliferation • oxidation-reduction process • response to toxic substance • response to herbicide • response to drug • porphyrin-containing compound metabolic process • ethylene metabolic process • lipid hydroxylation Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1543	13076
Ensembl	ENSG00000140465	ENSMUSG00000032315
UniProt	P04798	P00184
RefSeq (mRNA)	NM_000499 NM_001319216 NM_001319217	NM_001136059 NM_009992
RefSeq (protein)	NP_000490.1 NP_001306145.1 NP_001306146.1	NP_001129531.1 NP_034122.1
Location (UCSC)	Chr 15: 74.72 – 74.73 Mb	Chr 9: 57.7 – 57.7 Mb
PubMed search	[2]	[3]
Wikidata

Cytochrome P450, family 1, subfamily A, polypeptide 1 is a protein^[4] that in humans is encoded by the CYP1A1 gene.^[5] The protein is a member of the cytochrome P450 superfamily of enzymes.^[6]

Function

Metabolism of xenobiotics and drugs

CYP1A1 is involved in phase I xenobiotic and drug metabolism (one substrate of it is theophylline). It is inhibited by fluoroquinolones and macrolides and induced by aromatic hydrocarbons.^[7]

CYP1A1 is also known as AHH (aryl hydrocarbon hydroxylase). It is involved in the metabolic activation of aromatic hydrocarbons (polycyclic aromatic hydrocarbons, PAH), for example, benzo(a)pyrene (BP), by transforming it to an epoxide. In this reaction, the oxidation of benzo[a]pyrene is catalysed by CYP1A1 to form BP-7,8-epoxide, which can be further oxidized by epoxide hydrolase (EH) to form BP-7,8-dihydrodiol. Finally CYP1A1 catalyses this intermediate to form BP-7,8-dihydrodiol-9,10-epoxide, which is the ultimate carcinogen.^[7]

However, an in vivo experiment with gene-deficient mice has found that the hydroxylation of benzo(a)pyrene by CYP1A1 can have an overall protective effect on the DNA, rather than contributing to potentially carcinogenic DNA modifications. This effect is likely due to the fact that CYP1A1 is highly active in the intestinal mucosa, and thus inhibits infiltration of ingested benzo(a)pyrene carcinogen into the systemic circulation.^[8]

CYP1A1 metabolism of various foreign agents to carcinogens has been implicated in the formation of various types of human cancer.^[9][10]

Metabolism of endogenous agents

CYP1A1 also metabolizes polyunsaturated fatty acids into signaling molecules that have physiological as well as pathological activities. CYP1A1 has monoxygenase activity in that it metabolizes arachidonic acid to 19-hydroxyeicosatetraenoic acid (19-HETE) (see 20-Hydroxyeicosatetraenoic acid) but also has epoxygenase activity in that it metabolizes docosahexaenoic acid to epoxides, primarily 19R,20S-epoxyeicosapentaenoic acid and 19S,20R-epoxyeicosapentaenoic acid isomers (termed 19,20-EDP) and similarly metabolizes eicosapentaenoic acid to epoxides, primarily 17R,18S-eicosatetraenic acid and 17S,18R-eicosatetraenic acid isomers (termed 17,18-EEQ).^[11] 19-HETE is an inhibitor of 20-HETE, a broadly active signaling molecule, e.g. it constricts arterioles, elevates blood pressure, promotes inflammation responses, and stimulates the growth of various types of tumor cells; however the in vivo ability and significance of 19-HETE in inhibiting 20-HETE has not been demonstrated (see 20-Hydroxyeicosatetraenoic acid). The EDP (see Epoxydocosapentaenoic acid) and EEQ (see epoxyeicosatetraenoic acid) metabolites have a broad range of activities. In various animal models and in vitro studies on animal and human tissues, they decrease hypertension and pain perception; suppress inflammation; inhibit angiogenesis, endothelial cell migration and endothelial cell proliferation; and inhibit the growth and metastasis of human breast and prostate cancer cell lines.^{[12][13][14][15]} It is suggested that the EDP and EEQ metabolites function in humans as they do in animal models and that, as products of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid, the EDP and EEQ metabolites contribute to many of the beneficial effects attributed to dietary omega-3 fatty acids.^[12][15][16] EDP and EEQ metabolites are short-lived, being inactivated within seconds or minutes of formation by epoxide hydrolases, particularly soluble epoxide hydrolase, and therefore act locally. CYP1A1 is one of the main extra-hepatic cytochrome P450 enzymes; it is not regarded as being a major contributor to forming the cited epoxides^[15] but could act locally in certain tissues such as the intestine and in certain cancers to do so.

Regulation

The expression of the CYP1A1 gene, along with that of CYP1A2/1B1 genes, is regulated by a heterodimeric transcription factor that consist of the aryl hydrocarbon receptor, a ligand activated transcription factor, and the aryl hydrocarbon receptor nuclear translocator.^[17] In the intestine, but not the liver, CYP1A1 expression moreover depends on TOLL-like receptor 2 (TLR2),^[18] which recognizes bacterial surface structures such as lipoteichoic acid.

Polymorphisms

Several polymorphisms have been identified in CYP1A1, some of which lead to more highly inducible AHH activity. CYP1A1 polymorphisms include:^{[19][20][21][22]}

• M1, T→C substitution at nucleotide 3801 in the 3'-non-coding region
• M2, A→G substitution at nucleotide 2455 leading to an amino acid change of isoleucine to valine at codon 462
• M3, T→C substitution at nucleotide 3205 in the 3'-non-coding region
• M4, C→A substitution at nucleotide 2453 leading to an amino acid change of threonine to asparagine at codon 461

The highly inducible forms of CYP1A1 are associated with an increased risk of lung cancer in smokers. (Reference = Kellerman et al., New Eng J Med 1973:289;934-937) Light smokers with the susceptible genotype CYP1A1 have a sevenfold higher risk of developing lung cancer compared to light smokers with the normal genotype.

References

Further reading