CYP2E1

Protein-coding gene in the species Homo sapiens

CYP2E1

Available structures PDB

Ortholog search: PDBe RCSB

List of PDB id codes

3E4E, 3E6I, 3GPH, 3KOH, 3LC4, 3T3Z

Identifiers Aliases

CYP2E1, CPE1, CYP2E, P450-J, P450C2E, cytochrome P450 family 2 subfamily E member 1

External IDs

OMIM: 124040 MGI: 88607 HomoloGene: 68089 GeneCards: CYP2E1

EC number

1.14.13.n7

Gene location (Human)

Chromosome 10 (human)

Chr.

Chromosome 10 (human)Chromosome 10 (human)Genomic location for CYP2E1Genomic location for CYP2E1

Band

10q26.3

Start

133,520,406 bp

End

133,561,220 bp

Gene location (Mouse)

Chromosome 7 (mouse)

Chr.

Chromosome 7 (mouse)Chromosome 7 (mouse)Genomic location for CYP2E1Genomic location for CYP2E1

Band

7 F4|7 85.94 cM

Start

140,343,652 bp

End

140,354,900 bp

RNA expression pattern Bgee Human Mouse (ortholog)

Top expressed inright lobe of liver
body of pancreas
right uterine tube
skin of abdomen
endothelial cell
middle temporal gyrus
Brodmann area 9
prefrontal cortex
cavity of mouth
thymusTop expressed inleft lobe of liver
white adipose tissue
subcutaneous adipose tissue
intercostal muscle
kidney
ankle joint
digastric muscle
ankle
carotid body
parotid glandMore reference expression data

BioGPS

More reference expression data

Gene ontology

Molecular function
iron ion binding
oxygen binding
arachidonic acid epoxygenase 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
monooxygenase activity
heme binding
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen
enzyme binding
oxidoreductase activity
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, NAD(P)H as one donor, and incorporation of one atom of oxygen
steroid hydroxylase activity
Hsp70 protein binding
Hsp90 protein binding
Cellular component
organelle membrane
endoplasmic reticulum membrane
intracellular membrane-bounded organelle
membrane
intrinsic component of endoplasmic reticulum membrane
Golgi membrane
endoplasmic reticulum
mitochondrion
cytoplasm
mitochondrial inner membrane
Biological process
steroid metabolic process
epoxygenase P450 pathway
response to ozone
heterocycle metabolic process
response to organonitrogen compound
monoterpenoid metabolic process
xenobiotic metabolic process
response to ethanol
triglyceride metabolic process
carbon tetrachloride metabolic process
halogenated hydrocarbon metabolic process
benzene metabolic process
long-chain fatty acid biosynthetic process
response to bacterium
organic acid metabolic process
Sources:Amigo / QuickGO

Orthologs Species

HumanMouse

Entrez

1571

13106

Ensembl

ENSG00000130649

ENSMUSG00000025479

UniProt

P05181

Q05421

RefSeq (mRNA)

NM_000773

NM_021282

RefSeq (protein)

NP_000764

NP_067257

Location (UCSC)

Chr 10: 133.52 – 133.56 MbChr 7: 140.34 – 140.35 Mb

PubMed search

WikidataView/Edit HumanView/Edit Mouse

Cytochrome P450 2E1 (abbreviated CYP2E1, EC 1.14.13.n7) is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. This class of enzymes is divided up into a number of subcategories, including CYP1, CYP2, and CYP3, which as a group are largely responsible for the breakdown of foreign compounds in mammals.

While CYP2E1 itself carries out a relatively low number of these reactions (~4% of known P450-mediated drug oxidations), it and related enzymes CYP1A2 and CYP3A4 are responsible for the breakdown of many toxic environmental chemicals and carcinogens that enter the body, in addition to basic metabolic reactions such as fatty acid oxidations.

CYP2E1 protein localizes to the endoplasmic reticulum and is induced by ethanol, the diabetic state, and starvation. The enzyme metabolizes both endogenous substrates, such as ethanol, acetone, and acetal, as well as exogenous substrates including benzene, carbon tetrachloride, ethylene glycol, and nitrosamines which are premutagens found in cigarette smoke. Due to its many substrates, this enzyme may be involved in such varied processes as gluconeogenesis, hepatic cirrhosis, diabetes, and cancer.

Selected residues in the active site of CYP2E1. Created using 3E4E (bound to inhibitor 4-methyl pyrazole)

.

Regulation

Genetic regulation

In humans, the CYP2E1 enzyme is encoded by the CYP2E1 gene. The enzyme has been identified in fetal liver, where it is posited to be the predominant ethanol-metabolizing enzyme, and may be connected to ethanol-mediated teratogenesis. In rats, within one day of birth the hepatic CYP2E1 gene is activated transcriptionally.

CYP2E1 expression is easily inducible, and can occur in the presence of a number of its substrates, including ethanol, isoniazid, tobacco, isopropanol, benzene, toluene, and acetone. For ethanol specifically, it seems that there exist two stages of induction, a post-translational mechanism for increased protein stability at low levels of ethanol and an additional transcriptional induction at high levels of ethanol.

Chemical regulation

CYP2E1 is inhibited by a variety of small molecules, many of which act competitively. Two such inhibitors, indazole and 4-methylpyrazole, coordinate with the active site\’s iron atom and were crystallized with recombinant human CYP2E1 in 2008 to give the first true crystal structures of the enzyme. Other inhibitors include diethyldithiocarbamate (in cancer), and disulfiram (in alcoholism).

Disease relevance

CYP2E1 is expressed in high levels in the liver, where it works to clear toxins from the body. In doing so, CYP2E1 bioactivates a variety of common anesthetics, including paracetamol (acetaminophen), halothane, enflurane, and isoflurane. The oxidation of these molecules by CYP2E1 can produce harmful substances such as trifluoroacetic acid chloride from halothane or NAPQI from paracetamol (acetaminophen) and is a major reason for their observed hepatotoxicity in patients.

CYP2E1 and other cytochrome P450 enzymes can inadvertently produce reactive oxygen species (ROS) in their active site when catalysis is not coordinated correctly, resulting in potential lipid peroxidation as well as protein and DNA oxidation. CYP2E1 is particularly susceptible to this phenomenon compared to other P450 enzymes, suggesting that its expression levels may be important for negative physiological effects observed in a number of disease states.

CYP2E1 expression levels have been correlated with a variety of dietary and physiological factors, such as ethanol consumption, diabetes, fasting, and obesity. It appears that cellular levels of the enzyme may be controlled by the molecular chaperone HSP90, which upon association with CYP2E1 allows for transport to the proteasome and subsequent degradation. Ethanol and other substrates may disrupt this association, leading to the higher expression levels observed in their presence. The increased expression of CYP2E1 accompanying these health conditions may therefore contribute to their pathogenesis by increasing the rate of production of ROS in the body.

According to a 1995 publication by Y Hu et al., a study in rats revealed a 8- to 9-fold elevation of CYP2E1 with fasting alone, compared to a 20-fold increase in enzyme level accompanied by a 16-fold increase in total catalytic capacity in rats who were both fasted and given large quantities of ethanol for 3 consecutive days. Starvation appears to upregulate CYP2E1 mRNA production in liver cells while alcohol seems to stabilize the enzyme itself post-translation and thus protect it from degradation by normal cellular proteolytic processes, giving the two an independent synergistic effect.

Applications

Trees have been genetically engineered to overexpress rabbit CYP2E1 enzyme. These transgenic trees have been used to remove pollutants from groundwater, a process known as phytoremediation.

0

Leave a Reply

Cart

loader
Top
0