Biology:CYP2E1

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1]

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.[2]

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.[3]

Function

CYP2E1 is a membrane protein expressed in high levels in the liver, where it composes nearly 50% of the total hepatic cytochrome P450 mRNA[4] and 7% of the hepatic cytochrome P450 protein.[5] The liver is therefore where most drugs undergo deactivation by CYP2E1, either directly or by facilitated excretion from the body.

CYP2E1 enzyme metabolizes mostly small, polar molecules, including toxic laboratory chemicals such as dimethylformamide, aniline, and halogenated hydrocarbons (see table below). While these oxidations are often of benefit to the body, certain carcinogens and toxins are bioactivated by CYP2E1, implicating the enzyme in the onset of hepatotoxicity caused by certain classes of drugs (see disease relevance section below).

CYP2E1 also plays a role in several important metabolic reactions, including the conversion of ethanol to acetaldehyde and to acetate in humans,[6] where it works alongside alcohol dehydrogenase and aldehyde dehydrogenase. In the conversion sequence of acetyl-CoA to glucose, CYP2E1 transforms acetone via hydroxyacetone (acetol) into propylene glycol and methylglyoxal, the precursors of pyruvate, acetate and lactate.[7][8][9]

CYP2E1 also carries out the metabolism of endogenous fatty acids such as the ω-1 hydroxylation of fatty acids such as arachidonic acid, involving it in important signaling pathways that may link it to diabetes and obesity.[10] Thus, it acts as a monooxygenase to metabolize arachidonic acid to 19-hydroxyeicosatetraenoic acid (19-HETE) (see 20-Hydroxyeicosatetraenoic acid). However, it also acts as an epoxygenase activity to metabolize docosahexaenoic acid to epoxides, primarily 19R,20S-epoxyeicosapentaenoic acid and 19S,20R-epoxyeicosapentaenoic acid isomers (termed 19,20-EDP) and eicosapentaenoic acid to epoxides, primarily 17R,18S-eicosatetraenoic acid and 17S,18R-eicosatetraenoic acid isomers (termed 17,18-EEQ).[11] 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.[12][13][14][15] 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.[12][15][16] 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. CYP2E1 is not regarded as being a major contributor to forming the cited epoxides[15] but could act locally in certain tissues to do so.

Substrates

Following is a table of selected substrates of CYP2E1. Where classes of agents are listed, there may be exceptions within the class.

Selected substrates of CYP2E1
Substrates

Structure

CYP2E1 exhibits structural motifs common to other human membrane-bound cytochrome P450 enzymes, and is composed of 12 major α-helices and 4 β-sheets with short intervening helices interspersed between the two.[10] Like other enzymes of this class, the active site of CYP2E1 contains an iron atom bound by a heme center which mediates the electron transfer steps necessary to carry out oxidation of its substrates. The active site of CYP2E1 is the smallest observed in human P450 enzymes, with its small capacity attributed in part to the introduction of an isoleucine at position 115. The side-chain of this residue protrudes out above the heme center, restricting active site volume compared to related enzymes that have less bulky residues at this position.[10] T303, which also protrudes into the active site, is particularly important for substrate positioning above the reactive iron center and is hence highly conserved by many cytochrome P450 enzymes.[10] Its hydroxyl group is well-positioned to donate a hydrogen bond to potential acceptors on the substrate, and its methyl group has also been implicated in the positioning of fatty acids within the active site.[21],[22] A number of residues proximal to the active site including L368 help make up a constricted, hydrophobic access channel which may also be important for determining the enzyme's specificity towards small molecules and ω-1 hydroxylation of fatty acids.[10]

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.[23] 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.[24] 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,[18] isoniazid,[18] tobacco,[25] isopropanol,[2] benzene,[2] toluene,[2] and acetone.[2] 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.[26]

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.[10] Other inhibitors include diethyldithiocarbamate[17] (in cancer), and disulfiram[18] (in alcoholism).

Disease relevance

CYP2E1 is expressed in high levels in the liver, where it works to clear toxins from the body.[4][5] In doing so, CYP2E1 bioactivates a variety of common anesthetics, including paracetamol (acetaminophen), halothane, enflurane, and isoflurane.[2] The oxidation of these molecules by CYP2E1 can produce harmful substances such as trifluoroacetic acid chloride from halothane [27] 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.[10] 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.[10]

CYP2E1 expression levels have been correlated with a variety of dietary and physiological factors, such as ethanol consumption,[28] diabetes,[29] fasting,[30] and obesity.[31] 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.[32] 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.[10]

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.[33]

See also

References

  1. ↑ "Homology modelling of human CYP2E1 based on the CYP2C5 crystal structure: investigation of enzyme-substrate and enzyme-inhibitor interactions". Toxicology in Vitro 17 (1): 93–105. Feb 2003. doi:10.1016/s0887-2333(02)00098-x. PMID 12537967. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 "Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors". Drug Metabolism Reviews 29 (1–2): 413–580. 1997. doi:10.3109/03602539709037591. PMID 9187528. 
  3. ↑ Template:NCBI RefSeq
  4. ↑ 4.0 4.1 "Reverse transcriptase-PCR quantification of mRNA levels from cytochrome (CYP)1, CYP2 and CYP3 families in 22 different human tissues". Pharmacogenetics and Genomics 17 (9): 731–42. Sep 2007. doi:10.1097/FPC.0b013e32810f2e58. PMID 17700362. 
  5. ↑ 5.0 5.1 "Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians". The Journal of Pharmacology and Experimental Therapeutics 270 (1): 414–23. Jul 1994. PMID 8035341. 
  6. ↑ "Genetic polymorphisms in the 5'-flanking region change transcriptional regulation of the human cytochrome P450IIE1 gene". Journal of Biochemistry 110 (4): 559–65. Oct 1991. doi:10.1093/oxfordjournals.jbchem.a123619. PMID 1778977. 
  7. ↑ Glew, Robert H. "You Can Get There From Here: Acetone, Anionic Ketones and Even-Carbon Fatty Acids can Provide Substrates for Gluconeogenesis". http://www.bioline.org.br/request?np10002. 
  8. ↑ "Propanediol metabolism and its relation to lactic acid metabolism". Annals of the New York Academy of Sciences 119 (3): 957–73. Jul 1965. doi:10.1111/j.1749-6632.1965.tb47455.x. PMID 4285478. Bibcode: 1965NYASA.119..957M. 
  9. ↑ "Toxicology, metabolism, and biochemistry of 1,2-propanediol". Toxicol Appl Pharmacol 21 (1): 102–111. 1972. doi:10.1016/0041-008X(72)90032-4. PMID 4553872. 
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 "Structures of human cytochrome P-450 2E1. Insights into the binding of inhibitors and both small molecular weight and fatty acid substrates". The Journal of Biological Chemistry 283 (48): 33698–707. Nov 2008. doi:10.1074/jbc.M805999200. PMID 18818195. 
  11. ↑ "CYP-eicosanoids--a new link between omega-3 fatty acids and cardiac disease?". Prostaglandins & Other Lipid Mediators 96 (1–4): 99–108. Nov 2011. doi:10.1016/j.prostaglandins.2011.09.001. PMID 21945326. 
  12. ↑ 12.0 12.1 "The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease". Pharmacological Reviews 66 (4): 1106–40. Oct 2014. doi:10.1124/pr.113.007781. PMID 25244930. 
  13. ↑ "Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer". Progress in Lipid Research 53: 108–23. Jan 2014. doi:10.1016/j.plipres.2013.11.003. PMID 24345640. 
  14. ↑ "Soluble epoxide hydrolase: A potential target for metabolic diseases". Journal of Diabetes 8 (3): 305–13. Dec 2015. doi:10.1111/1753-0407.12358. PMID 26621325. 
  15. ↑ 15.0 15.1 15.2 "The role of long chain fatty acids and their epoxide metabolites in nociceptive signaling". Prostaglandins & Other Lipid Mediators 113–115: 2–12. Oct 2014. doi:10.1016/j.prostaglandins.2014.09.001. PMID 25240260. 
  16. ↑ "Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway". Journal of Lipid Research 55 (6): 1150–1164. Mar 2014. doi:10.1194/jlr.M047357. PMID 24634501. 
  17. ↑ 17.0 17.1 17.2 17.3 17.4 Swedish environmental classification of pharmaceuticals Facts for prescribers (Fakta för förskrivare)
  18. ↑ 18.00 18.01 18.02 18.03 18.04 18.05 18.06 18.07 18.08 18.09 18.10 18.11 18.12 18.13 18.14 Flockhart DA (2007). "Drug Interactions: Cytochrome P450 Drug Interaction Table". Indiana University School of Medicine. http://medicine.iupui.edu/flockhart/table.htm.  Retrieved on July 2011
  19. ↑ "Assessment of Zopiclone". World Health Organization. 2006. p. 9 (Section 5. Pharmacokinetics). https://www.who.int/medicines/areas/quality_safety/4.6ZopicloneCritReview.pdf. 
  20. ↑ "Verapamil: Drug information. Lexicomp". https://www.uptodate.com/contents/verapamil-drug-information. 
  21. ↑ "Replacement of Thr-303 of P450 2E1 with serine modifies the regioselectivity of its fatty acid hydroxylase activity". Journal of Biochemistry 113 (1): 7–12. Jan 1993. doi:10.1093/oxfordjournals.jbchem.a124006. PMID 8454577. 
  22. ↑ "Different mechanisms of regioselection of fatty acid hydroxylation by laurate (omega-1)-hydroxylating P450s, P450 2C2 and P450 2E1". Journal of Biochemistry 115 (2): 338–44. Feb 1994. doi:10.1093/oxfordjournals.jbchem.a124339. PMID 8206883. 
  23. ↑ "Regional mapping of short tandem repeats on human chromosome 10: cytochrome P450 gene CYP2E, D10S196, D10S220, and D10S225". Genomics 18 (3): 702–4. Dec 1993. doi:10.1016/S0888-7543(05)80378-7. PMID 8307581. 
  24. ↑ "Human lymphocyte cytochrome P450 2E1, a putative marker for alcohol-mediated changes in hepatic chlorzoxazone activity". Drug Metabolism and Disposition 25 (12): 1429–35. Dec 1997. PMID 9394034. 
  25. ↑ "Smoking in patients receiving psychotropic medications: a pharmacokinetic perspective". CNS Drugs 15 (6): 469–94. 2001. doi:10.2165/00023210-200115060-00005. PMID 11524025. 
  26. ↑ "Microsomal ethanol-oxidizing system (MEOS): the first 30 years (1968-1998)--a review". Alcoholism: Clinical and Experimental Research 23 (6): 991–1007. Jun 1999. doi:10.1111/j.1530-0277.1999.tb04217.x. PMID 10397283. 
  27. ↑ "Halothane hepatitis". British Journal of Anaesthesia 67 (1): 84–99. Jul 1991. doi:10.1093/bja/67.1.84. PMID 1859766. 
  28. ↑ "Markedly enhanced cytochrome P450 2E1 induction and lipid peroxidation is associated with severe liver injury in fish oil-ethanol-fed rats". Alcoholism: Clinical and Experimental Research 18 (5): 1280–5. Oct 1994. doi:10.1111/j.1530-0277.1994.tb00119.x. PMID 7847620. 
  29. ↑ "The effect of bamboo extract on hepatic biotransforming enzymes--findings from an obese-diabetic mouse model". Journal of Ethnopharmacology 133 (1): 37–45. Jan 2011. doi:10.1016/j.jep.2010.08.062. PMID 20832461. 
  30. ↑ "Ethanol-, fasting-, and acetone-inducible cytochromes P-450 in rat liver: regulation and characteristics of enzymes belonging to the IIB and IIE gene subfamilies". Biochemistry 27 (6): 1925–34. Mar 1988. doi:10.1021/bi00406a019. PMID 3378038. 
  31. ↑ "Induction of cytochrome P450IIE1 in the obese overfed rat". Molecular Pharmacology 39 (3): 275–80. Mar 1991. PMID 2005876. 
  32. ↑ "The possible mechanisms of CYP2E1 interactions with HSP90 and the influence of ethanol on them" (in en). BMC Structural Biology 12 (1): 33. 2012-12-17. doi:10.1186/1472-6807-12-33. PMID 23241420. 
  33. ↑ "Enhanced phytoremediation of volatile environmental pollutants with transgenic trees". Proceedings of the National Academy of Sciences of the United States of America 104 (43): 16816–21. Oct 2007. doi:10.1073/pnas.0703276104. PMID 17940038. Bibcode: 2007PNAS..10416816D. 

Further reading

External links



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