Cytochrome P450, family 1, subfamily A, polypeptide 1 is a
protein[5] that in humans is encoded by the CYP1A1gene.[6] The protein is a member of the
cytochrome P450 superfamily of enzymes.[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 (BaP), by transforming it to an
epoxide. In this reaction, the oxidation of benzo[a]pyrene is catalysed by CYP1A1 to form BaP-7,8-epoxide, which can be further oxidized by
epoxide hydrolase (EH) to form BaP-7,8-dihydrodiol. Finally, CYP1A1 catalyses this intermediate to form BaP-7,8-dihydrodiol-9,10-epoxide, which is a
carcinogen.[9]
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.[10]
CYP1A1 metabolism of various foreign agents to
carcinogens has been implicated in the formation of various types of human cancer.[11][12]
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-eicosatetraenoic acid and 17S,18R-eicosatetraenoic acid isomers (termed 17,18-EEQ).[13] Synthesis of
12(S)-HETE by CYP1A1 has also been demonstrated.[14] 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.[15][16][17][18] 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.[15][18][19] 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[18] 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.[20]
In the intestine, but not the liver, CYP1A1 expression moreover depends on TOLL-like receptor 2 (
TLR2),[21] which recognizes bacterial surface structures such as
lipoteichoic acid. Additionally, the tumour suppressor
p53 has been shown to impact CYP1A1 expression thereby modulating the metabolic activation of several environmental carcinogens such as PAHs.[22]
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.
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