CYP2E1s Role In Drug Metabolism Biology Essay

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CYP2E1 has relevance in chemical toxicity and carcinogenicity so it has been studied for many years as of now. Despite the fact that CYP2E1 gene has number of SNPs (single nucleotide polymorphisms), it is well conserved in mammals and there are no polymorphism that is known because of CYP2E1 gene inactivity in human or animal models. Moreover, there is not much distinctions in the enzymatic activity among different species like humans, rabbits, rats, and mice which leads us to thought of CYP2E1 having an important functional activity in mammals.

Leiber et al. found that the oxidation of ethanol was catalyzed by the membrane fractions of microsomes which lead to the designation of new term i.e. 'Microsomal ethanol-oxidizing system (MEOS) since this was bound to membrane, required NADPH and was inactivated by Carbon monoxide which is quite uncommon to alcohol dehydrogenase. From this experiment they also obtained result showing that MEOS activity was induced by administering ethanol to rats and this lead to increased clearance of alcohol that is no blocked by pyrazole (Pyrazole is an inhibitor of ADH). These results lead to major advancement in alcohol field with substantial clinical implications.

The first P450 which was capable of ethanol oxidation was obtained and purified from rabbit by Koop et al. Following this, the rat ortholog was extracted and was found to have enzymatic activity towards aniline p-hydroxylation by Ryan et al. After some years, studies performed using purified recombinant P450 revealed that CYP2E1 metabolizes a large no of low molecular weight chemicals like Acetaldehyde, acetaminophen, diethyl ether, glycerol, ethylene glycol,etc many of which are low molecular carcinogenic agents. Therefore, we can say that CYP2E1 is important for toxicological and carcinogenic properties.

CYP2E1 Transcriptional Control

Ueno and Gonzalez (1990) suggested the factors that regulate the developmental activation of CYP2E1 gene transcription and the position at which these transcription factors bind to the promoter region in this gene. Further studies in this regard established the fact that rat and human CYP2E1 genes are under controlled regulation of liver enriched transcription factor which is also known as HNF1-alpha (Hepatocyte nuclear factor 1 alpha). Despite these research evidences recently there are results obtained that shows that regulation of CYP2E1 is not solely Hnf1α dependent as the deletion of β-catenin gene in rats showed almost complete loss of CYP2E1 mRNA in liver without changing the level of Hnf1α. The main role of catenin on a transcriptional coactivator required for CYP2E1 activation by Hnf1α is among the available possibilities.

CYP2E1 Stabilization

Substrates like acetone, ethanol and pyrazole are all inducers of CYP2E1 activity and proteins via a post translational mechanism revealed by in vivo labeling of presence of substrate. Others found that electron transfer actually increases proteosomal degration of CYP2E1.

There are two pathways known: lysosomal pathway and the proteosome pathway that can participate in the degradation proteins from membranes. Membrane proteins are degraded by the lysosomes through fusion of ER with lysosomal membranes and this process is slower than that of the proteosome pathway. It has been shown in cell lines that CYP2E1 degradation can occur via an ubiquitin-independent proteosomal pathway. Due to the established biphasic nature of CYP2E1 turnover found in vivo, it is alluring to guess that, in the presence of substrate, CYP2E1 may not be subject to the more rapid phase of turnover via proteosomes due either to confiscation of the enzyme in certain regions of the ER or to altered conformation of the protein as a result of substrate binding, or a combination. Lysosomal pathway would follow to function in the presence of substrate. The prompt for degradation via latter pathway is not known but could due to phosphorylation or alteration in the folding pattern of the protein. It should also be considered that substrate-induced stabilization has not been confirmed for other P450s. Long-term in vivo exposure to the substrate is required for a condition that could be achieved with chronic drug treatment to achieve significant P450 stabilization.

CYP2E1 Null mice

  Past evidences suggests that CYP2E1 has an important role in mammals. It is constitutively expressed in hepatic tissues and participates in gluconeogenesis process. The enzyme and its activities are well conserved in humans and other experimental animals such as rabbits, rats, and mice. No functional polymorphism is found in humans or any animal model that substantially alters catalytic activity of CYP2E1. Thus, it was thought that any important function for this P450 would be revealed by phenotypes obtained from Cyp2e1 gene knockout mice. However, this model has been of great value in determining the role of CYP2E1 in chemical toxicity and carcinogenicity.

CYP2E1 role in Carcinogenesis

Azoxymethane is colon carcinogen that is is activated by CYP2E1 to its metabolite that forms addcuts in colon and extrahepatic tissues. In extrahepatic tissues, including colon, non-P450 enzymes such as alcohol dehydrogenase can activate MAM. Colonic aberrant crypt foci, precursors to colon polyps, were also lower in the null mice treated with AOM, in agreement with the DNA adduct. CYP2E1 is a highly liver-enriched enzyme but is not significantly expressed in the colon. There is a belief that MAM, produced in the liver, is transported to the colon where it is further converted to the methyl diazonium-alkylating agent responsible for producing the DNA adducts, which are likely precursors of the colon cancer.

CYP2E1 role in Alcohol metabolism

Gong et al. showed that CYP2E1 plays a vital role in alcohol metabolism and liver damage due to alcohol by producing O2-· and H2O2 which deplete the intracellular glutathione levels and causes cell damage. Moreover, these reactive oxygen species produces radicals like hydroxyl that are powerful oxidants. Also lipid peroxides formed from ROS form adducts with nucleophiles in cell environment like protein and nucleic acids resulting in cell damage. Some research in this field states that cell lines like HepG2 which overexpresses this enzyme cause elevation in oxidative stress and also activation of p38 mitogen pathway and induces erythroid like factor 2. Although of little consequence to liver toxicity there are subtle difference observed in DNA damage. Because of difference in liver architecture it is accepted that alcohol induced hepatic damage differs in mice and other rodent models.

CYP2E1 role in Acetaminophen toxicity

Raucy et al showed that CYP2E1 is important enzyme that plays a role in activation of Acetaminophen conversion to NAPQI which is an active metabolite responsible for acetaminophen toxicity. This evidence agrees with the fact that ethanol enhances the acetaminophen induced hepatotoxicity in rats and also in humans the drug disulfiram which is CYP2E1 inhibitor decreases the clearance of acetaminophen.

CYP2E1: future study prospects

Metabolomics:  The analysis of small molecules in biological fluids to determine the outcome of altered metabolism or the response to pathophysiological stimuli such as xenobiotic. These measurements made on small molecules are carried out by chromatographic methods which are methods that are sensitive for molecules below 800 Da. 1H NMR has been used in most studies to date because it allows the precise determination of the structure and quantity of chemicals in a biological samples. Biomarkers can be identified that determine organ-specific drug toxicity by use of animal models. 1H NMR metabolomics may also be of value to diagnose diseases such as atherosclerosis, cancer, and neurological disorders.

Metabolomics is only possible when we combine it with powerful data analysis machine. Multiple samples is subjected to data sourcing which is then followed by chemo metric and multivariate analysis to extract relevant information that shows the differences between samples or groups. Principal components analysis (PCA) is generally used in metabolomics studies. The simultaneous analysis and comparison of thousands of ions from two or more groups is possible only due to PCA.

1H NMR yields lacks the sensitivity and resolution power to study low-abundance metabolites in complex combinations. Metabolomics can also be carried out by use of the more accessible LC-MS technology which does not give precise chemical structures and quantification in the absence of standards but allows the analysis and comparison of thousands of compounds.

Recently, an ultra-performance liquid chromatography-coupled time-of-flight mass spectrometry (UPLC-TOFMS) has been developed for use in metabolomics. This instrumentation lets the resolution and exact mass determinations of thousands of molecules in a biological sample where the quantities of biological materials such as serum and urine are scarce and is preferably matched for studies in rodent model systems. A urine specimen can typically give 5 to 10,000 ions that can be analyzed by PCA and are detected by the MS.

Conclusion

There are many more things that remains to be derived or developed to understand the mechanisms of regulation of the CYP2E1 gene although there have been a considerable progress made in recognizing the role of CYP2E1 in alcohol and chemical toxicity.

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