Cytochrome P450, family 1, subfamily A, polypeptide 1 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
[
] that in humans is encoded by the ''CYP1A1''
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 ...
.
[
] The protein is a member 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 ...
superfamily of enzymes.
[
]
Function
Metabolism of xenobiotics and drugs
CYP1A1 is involved in phase I
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 ...
and
drug metabolism
Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism (from the Greek xenos "stranger" and biotic "related to living beings") is the set o ...
(one substrate of it is
theophylline
Theophylline, also known as 1,3-dimethylxanthine, is a phosphodiesterase inhibiting drug used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma under a variety of brand names. As a member of the ...
). It is inhibited by
hesperetin
Hesperetin is the 4'-methoxy derivative of eriodictyol, a flavanone. Hesperetin's 7-O-glycoside, hesperidin, is a naturally occurring flavanon-glycoside, the main flavonoid in lemons and sweet oranges. Hesperetin (and naringenin, the parent flav ...
(a
flavonoid found in lime, sweet orange),
fluoroquinolone
A quinolone antibiotic is a member of a large group of broad-spectrum bacteriocidals that share a bicyclic core structure related to the substance 4-quinolone. They are used in human and veterinary medicine to treat bacterial infections, as wel ...
s and
macrolide
The Macrolides are a class of natural products that consist of a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Ma ...
s and induced by
aromatic hydrocarbons
Aromatic compounds, also known as "mono- and polycyclic aromatic hydrocarbons", are organic compounds containing one or more aromatic rings. The parent member of aromatic compounds is benzene. The word "aromatic" originates from the past groupin ...
.
[
]
CYP1A1 is also known as AHH (aryl hydrocarbon hydroxylase). It is involved in the metabolic activation of aromatic hydrocarbons (
polycyclic aromatic hydrocarbons
A polycyclic aromatic hydrocarbon (PAH) is a class of organic compounds that is composed of multiple aromatic rings. The simplest representative is naphthalene, having two aromatic rings and the three-ring compounds anthracene and phenanthrene. ...
, PAH), for example,
benzo yrene">yrene (BaP), by transforming it to an
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 ...
. In this reaction, the oxidation of benzo
yrene is catalysed by CYP1A1 to form BaP-7,8-epoxide, which can be further oxidized by
epoxide hydrolase
Epoxide hydrolases (EH's), also known as epoxide hydratases, are enzymes that metabolize compounds that contain an epoxide residue; they convert this residue to two hydroxyl residues through an epoxide hydrolysis reaction to form diol products. ...
(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
A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive subs ...
.
However, an ''in vivo'' experiment with gene-deficient mice has found that the hydroxylation of benzo
yrene 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
yrene carcinogen into the systemic circulation.
CYP1A1 metabolism of various foreign agents to
carcinogen
A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive subs ...
s has been implicated in the formation of various types of human cancer.
Metabolism of endogenous agents
CYP1A1 also metabolizes
polyunsaturated fatty acid
Polyunsaturated fatty acids (PUFAs) are fatty acids that contain more than one double bond in their backbone. This class includes many important compounds, such as essential fatty acids and those that give drying oils their characteristic proper ...
s 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
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 substr ...
activity in that it metabolizes
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
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 ...
s, primarily 19''R'',20''S''-epoxyeicosapentaenoic acid and 19''S'',20''R''-epoxyeicosapentaenoic acid isomers (termed 19,20-EDP) and similarly metabolizes
eicosapentaenoic acid
Eicosapentaenoic acid (EPA; also icosapentaenoic acid) is an omega-3 fatty acid. In physiological literature, it is given the name 20:5(n-3). It also has the trivial name timnodonic acid. In chemical structure, EPA is a carboxylic acid with a 20-c ...
to epoxides, primarily 17''R'',18''S''-eicosatetraenic acid and 17''S'',18''R''-eicosatetraenic acid isomers (termed 17,18-EEQ). Synthesis of
12(S)-HETE by CYP1A1 has also been demonstrated. 19-HETE is an inhibitor of 20-HETE, a broadly active signaling molecule, e.g. it constricts
arteriole
An arteriole is a small-diameter blood vessel in the microcirculation that extends and branches out from an artery and leads to capillaries.
Arterioles have muscular walls (usually only one to two layers of smooth muscle cells) and are the primar ...
s, elevates blood pressure, promotes
inflammation
Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
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
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 metab ...
) and EEQ (see
epoxyeicosatetraenoic acid
Epoxyeicosatetraenoic acids (EEQs or EpETEs) are a set of biologically active epoxides that various cell types make by metabolizing the omega 3 fatty acid, eicosapentaenoic acid (EPA), with certain cytochrome P450 epoxygenases. These epoxygenases ...
) 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.
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 acid
Omega−3 fatty acids, also called Omega-3 oils, ω−3 fatty acids or ''n''−3 fatty acids, are polyunsaturated fatty acids (PUFAs) characterized by the presence of a double bond, three atoms away from the terminal methyl group in their chem ...
s, docosahexaenoic acid and eicosapentaenoic acid, the EDP and EEQ metabolites contribute to many of the beneficial effects attributed to dietary omega-3 fatty acids.
EDP and EEQ metabolites are short-lived, being inactivated within seconds or minutes of formation by
epoxide hydrolase
Epoxide hydrolases (EH's), also known as epoxide hydratases, are enzymes that metabolize compounds that contain an epoxide residue; they convert this residue to two hydroxyl residues through an epoxide hydrolysis reaction to form diol products. ...
s, particularly
soluble epoxide hydrolase
Soluble epoxide hydrolase (sEH) is a bifunctional enzyme that in humans is encoded by the EPHX2 gene. sEH is a member of the epoxide hydrolase family. This enzyme, found in both the cytosol and peroxisomes, binds to specific epoxides and convert ...
, 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
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
The aryl hydrocarbon receptor (also known as AhR, AHR, ahr, ahR, or dioxin receptor) is a protein that in humans is encoded by the AHR gene. The aryl hydrocarbon receptor is a transcription factor that regulates gene expression. It was originall ...
, a ligand activated
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...
, and the
aryl hydrocarbon receptor nuclear translocator
The ARNT gene encodes the aryl hydrocarbon receptor nuclear translocator protein that forms a complex with ligand-bound aryl hydrocarbon receptor (AhR), and is required for receptor function. The encoded protein has also been identified as the be ...
.
[
]
In the intestine, but not the liver, CYP1A1 expression moreover depends on TOLL-like receptor 2 (
TLR2
Toll-like receptor 2 also known as TLR2 is a protein that in humans is encoded by the ''TLR2'' gene. TLR2 has also been designated as CD282 (cluster of differentiation 282). TLR2 is one of the toll-like receptors and plays a role in the immune sys ...
), which recognizes bacterial surface structures such as
lipoteichoic acid Lipoteichoic acid (LTA) is a major constituent of the cell wall of gram-positive bacteria. These organisms have an inner (or cytoplasmic) membrane and, external to it, a thick (up to 80 nanometer) peptidoglycan layer. The structure of LTA varies ...
. Additionally, the tumour suppressor
p53
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
has been shown to impact ''CYP1A1'' expression thereby modulating the metabolic activation of several environmental carcinogens such as PAHs.
Polymorphisms
Several
polymorphisms have been identified in CYP1A1, some of which lead to more highly inducible AHH activity. CYP1A1
polymorphisms include:
[
]
* M1,
T→
C substitution at
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecule ...
3801 in the 3'-
non-coding
Non-coding DNA (ncDNA) sequences are components of an organism's DNA that do not encode protein sequences. Some non-coding DNA is transcribed into functional non-coding RNA molecules (e.g. transfer RNA, microRNA, piRNA, ribosomal RNA, and regula ...
region
* M2,
A→
G substitution at nucleotide 2455 leading to an amino acid change of
isoleucine to
valine
Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotona ...
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
Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...
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
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