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- Table of Contents
Facts about Cytochrome P450 2C8.
It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids.
Human | |
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Gene Name: | CYP2C8 |
Uniprot: | P10632 |
Entrez: | 1558 |
Belongs to: |
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cytochrome P450 family |
CPC8; CYPIIC8; cytochrome P450 2C8; Cytochrome P450 form 1; Cytochrome P450 IIC2; Cytochrome P450 MP-12; Cytochrome P450 MP-20; cytochrome P450, family 2, subfamily C, polypeptide 8; cytochrome P450, subfamily IIC (mephenytoin 4-hydroxylase), polypeptide 8; EC 1.14.14.1; flavoprotein-linked monooxygenase; microsomal monooxygenase; MP-12/MP-20; P450 form 1; S-mephenytoin 4-hydroxylase; xenobiotic monooxygenase
Mass (kDA):
55.825 kDA
Human | |
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Location: | 10q23.33 |
Sequence: | 10; NC_000010.11 (95036772..95069497, complement) |
Endoplasmic reticulum membrane; Peripheral membrane protein. Microsome membrane; Peripheral membrane protein.
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The CYP2C8 gene is one of the most important human hepatic enzymes plays a key role in the metabolism of drugs. It also plays an important role in the metabolism of numerous important drugs, such as cerivastatin and Paclitaxel. There are numerous products on the market today that originate from herbs. This is why finding out their interactions with the CYP2C8 gene is a crucial safety concern.
The CYP2C8 gene is found in human colons and colorectal carcinoma cells. In humans the expression of the CYP2C8*3 gene can be inducible. Studies in the past have identified an association between changes in CYP2C8 gene expression and colon cancer. This study identifies a range of CYP2C8 genes that could be altered to target specific types of cancer.
Researchers conducted interviews with participants and collected blood samples during the study. Genomic DNA was extracted from peripheral leukocytes and used to study the CYP2C8*3 variant. This cDNA was then used for amplification-restriction procedures to determine whether the sample had the CYP2C8*3 allele. The PCR product has been purified and digested by endonucleaseXmnI. The CYP2C8*3 product did not undergo any digestion.
The CYP2C8*2 genetic variant, which is the most common in Africa is very widespread. It is also associated with the phenotype of a poor metabolizer. It extends the duration of the drug's half-life and increases the likelihood of adverse reactions. In the case of AQ it is found that CYP2C8*2 has six times lower intrinsic clearance of AQ than wild-type individuals. Similarly, there is indirect evidence that the CYP2C8*2 gene is linked to the incidence of CQ-resistant P. falciparum infections in Africa.
The CYP2C8 Gene is involved in the liver metabolism of chloroquine as well as amodiaquine. Patients with this gene variant have a higher incidence of drug-resistant parasites. The corresponding mutagenic substance is pfmdr1-86Y. The CYP2C8 gene has been linked to several drug-resistant genes and an inherited gene polymorphism.
The CYP2C8 gene has been identified as a significant enzyme for metabolizing drugs. The human liver produces a significant amount of CYP2C8 and can metabolize more than 100 drugs. CYP2C8 is able to process substances like amodiaquine as well as pioglitazone.
In addition to the metabolizers of drugs The CYP2C8 gene is also implicated in an important role in many human illnesses. Approximately 5% of all medications used in clinical trials are metabolized by CYP2C8. The increasing attention to this has led to the creation of new drugs and the study of CYP2C8 genetic polymorphisms. In addition the increasing number of CYP2C8 genetic polymorphisms have been associated with specific diseases and conditions.
A large portion of human populations have high levels of conservation for the CYP2C8 genes. The polymorphisms in it have been linked with paclitaxel 6-alpha enzyme activity in microsomes of human cells. Additionally, the CYP2C8 gene is involved in the metabolism of repaglinide as well as the paclitaxel. The CYP2C8 gene may be used in diagnostic tests to assess the risk of a patient developing a disease or drug interaction.
Inflammatory conditions can be cured by increasing the production of CYP2C8-derived EATs. These compounds, made from arachidonic acids via CYP enzymes, have been shown to possess anti-inflammatory properties. However, the precise mechanisms that EETs use to exert their anti-inflammatory effects are unclear. This is why further research is required to understand the enzymes' epoxygenase activities.
In rats exposed to smoking tobacco, soluble-epoxide-hydralase inhibitors (sEHIs) improve lung function and reduce inflammation. Although the mechanism behind sEHIs' action is not evident but it is believed that EETs can reduce lung damage caused by CSE by stabilizing antiinflammatory lipid Epoxides and inhibiting proinflammatory lipid-1.2-diols. While the precise mechanisms in the actions of sEHI and EETs remain largely unclear but evidence suggests that EETs could play a role in preventing COPD.
Although it isn't clear the mechanism behind EETs however, it has been proven that pregnant women have higher plasma levels of EETs than those who aren't. EETs are also detected in the fetal plasma three times more than in the maternal plasma, suggesting an involvement in the fetal blood vessel defense. EETs are also a key role in a range of physiological functions, including the stabilization and maintenance of the maternal-fetal ratio , as well as the stabilization of the vascular function.
EETs regulate the proliferation of endothelial cells by lowering blood pressure and decreasing intravascular volumes. They also influence the homeostasis of endoplasmicreticulum. They are also known to increase sodium excretion in the bloodstream. This could be a possible new treatment for hypertension. These compounds are extremely beneficial in the prevention of inflammation-related diseases.
CYP2C8-derived EEHT inhibits the phosphorylation process of JNK and ERK1/2. However, EETH-derived EETs are not able to affect the phosphorylation of ERK1/2. They may also protect against the apoptosis of cancerous cells by inhibiting the ERK1/2/p38 MAPK signalling pathways.
The mechanism by which EETs block NFkB-dependent transcription and reduce cytokines induced by TNF has not yet been completely understood. In mice, it is easier to comprehend the anti-inflammatory properties of the CYP2C8-derived EETs. In rodents, the overexpression pCMV-CYP2C8 within hepatocytes blocks cell proliferation and migration by more than half.
In humans, EETs appear to regulate blood pressure and contribute to kidney function and hypertension. These positive effects are the reason these therapeutics are derived from EET to treat these conditions. The development of these compounds could stop the progress of CKD to renal failure. It is likely to have a bright future. These compounds could be a promising target for a wide range of diseases. They can also shield the kidney from damage and stop the progress of renal failure.
CYP2C8-derived EEH inhibits breast cancer cell growth and migration. In addition, adenovirus-sEH inhibits EEH production. These are the results of three experiments that were conducted in triplicate. These results suggest that CYP2C8 derived EETs could be a significant defense against inflammation. They may help protect against various kinds of cancer and have anti-inflammatory properties.
The T172Da1 variant of CYP2C8 provides the largest neuroprotective effect against a-syn toxicity and reduces the loss of Nissl positive neurons by over 50%. While the T172Da1 variant is integrated into the AMPK system however, it has a predominant negative effect on AMPK. The low activity of the variant suggests that this variant could provide neuroprotection through its chronic low-activity mode.
It is well-known that the CYP2C8 protein plays crucial roles in regulating amyloid beta metabolism. CYP2C8 overactivity is observed in pretangle-bearing and tauopathies cells. The inhibition of CYP2C8 results in a reduction in this protein-synthesis. Neuroprotective effects are therefore seen in patients with this disorder if CYP2C8 levels are decreased.
Neuroprotective effects of AMPKa2 in vivo are known. It is part of the AMPK complex that protects the dopaminergic neuron in vitro. Incredibly, a variant of the CYP2C8 genes, known as T172Da1 has the lowest active catalytic function in the long term. However, it provides the most effective neuroprotection of dopaminergic neurons, and decreases the number of dystrophic neurons with aggregated a-syn.
The effects of AMPKa on neurodegeneration are not clear, but the inhibitory effect on AMPK signaling was evident. In the MPTP intoxication model inhibition of AMPKa increased neuronal degeneration by stimulating the formation of a-syn oligomers in primary neurons. In vitro and in vivo studies have shown that inhibition of AMPK causes neuronal death to rise.
AMPK activity decreases the toxicity of a-synuclein of the dopaminergic neuron in the nigral region. This is a significant finding for neuroprotective medications against PD. Parkinson's disease is a debilitating neurodegenerative disease characterized by motor symptoms and the loss of dopamine neuronal cells in the substantia nubla pars compacta. This disease is caused by the disintegration and accumulation of A-synuclein proteins that result in dysfunction of the basal Ganglia.
PMID: 3500169 by Okino S.T., et al. Characterization of multiple human cytochrome P-450 1 cDNAs. The chromosomal localization of the gene and evidence for alternate RNA splicing.
PMID: 3697070 by Kimura S., et al. cDNA and amino acid sequences of two members of the human P450IIC gene subfamily.