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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]

The CYP2 subfamily is responsible for the majority of P450-mediated drug metabolism in humans.[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 a large number of toxic environmental chemicals and carcinogens that enter the body, in addition to basic metabolic reactions such as fatty acid oxidations.[2]

Biological Function

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CYP2E1 is a membrane protein expressed in high levels in the liver, where it composes nearly 50% of the total hepatic cytochrome P450 mRNA[3] and 7% of the hepatic cytochrome P450 protein.[4] The liver is therefore where most drugs undergo deactivation by CYP2E1, either directly or by facilitated excretion from the body.

CYP2E1 metabolizes mostly small, polar molecules, including toxic lab 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,[5] 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.[6][7][8] CYP2E1 also carries out ω-1 hydroxylation of fatty acids such as arachidonic acid, involving it in important signaling pathways that may link it to diabetes and obesity.[9]

Substrates

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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

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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.[9] 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.[9] 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.[9] 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.[12],[13] 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.[9]

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

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Regulation

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Genetic regulation

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In humans, the CYP2E1 enzyme is encoded by the CYP2E1 gene.[14] 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.[15] 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[11], isoniazid[11], tobacco,[16] 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.[17]

Chemical regulation

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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.[9] Other inhibitors include diethyldithiocarbamate[10] (in cancer), and disulfiram[11] (in alcoholism).

Disease relevance

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CYP2E1 is expressed in high levels in the liver, where it works to clear toxins from the body.[3][4] In doing so, CYP2E1 bioactivates a variety of common anesthetics, including acetaminophen, halothane, enflurane, and isoflurane.[2] The oxidation of these molecules by CYP2E1 can produce harmful substances such as trifluoroacetic acid chloride,[18] 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.[9] 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.[9]

CYP2E1 expression levels have been correlated with a variety of dietary and physiological factors, such as ethanol consumption,[19] diabetes,[20] fasting[21], and obesity.[22] 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.[23] 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.[9]

Applications

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Trees have been genetically engineered to overexpress the CYP2E1 enzyme. These transgenic trees have been used to remove pollutants from groundwater, a process known as phytoremediation.[24]

See also

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References

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  1. ^ a b Lewis DF, Lake BG, Bird MG, Loizou GD, Dickins M, Goldfarb PS (Feb 2003). "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. PMID 12537967.
  2. ^ a b c d e f Rendic S, Di Carlo FJ (1997). "Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors". Drug Metabolism Reviews. 29 (1–2): 413–580. PMID 9187528.
  3. ^ a b Bièche I, Narjoz C, Asselah T, Vacher S, Marcellin P, Lidereau R, Beaune P, de Waziers I (Sep 2007). "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. doi:10.1097/FPC.0b013e32810f2e58. PMID 17700362.
  4. ^ a b Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP (Jul 1994). "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. PMID 8035341.
  5. ^ Hayashi S, Watanabe J, Kawajiri K (Oct 1991). "Genetic polymorphisms in the 5'-flanking region change transcriptional regulation of the human cytochrome P450IIE1 gene". Journal of Biochemistry. 110 (4): 559–65. PMID 1778977.
  6. ^ Glew, Robert H. "You Can Get There From Here: Acetone, Anionic Ketones and Even-Carbon Fatty Acids can Provide Substrates for Gluconeogenesis". Retrieved August 2013. {{cite web}}: Check date values in: |accessdate= (help)
  7. ^ Miller ON, Bazzano G (Jul 1965). "Propanediol metabolism and its relation to lactic acid metabolism". Annals of the New York Academy of Sciences. 119 (3): 957–73. Bibcode:1965NYASA.119..957M. doi:10.1111/j.1749-6632.1965.tb47455.x. PMID 4285478.
  8. ^ Ruddick JA (1972). "Toxicology, metabolism, and biochemistry of 1,2-propanediol". Toxicol App Pharmacol. 21: 102–111. doi:10.1016/0041-008X(72)90032-4.
  9. ^ a b c d e f g h i Porubsky PR, Meneely KM, Scott EE (Nov 2008). "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. doi:10.1074/jbc.M805999200. PMC 2586265. PMID 18818195.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  10. ^ a b c d e Swedish environmental classification of pharmaceuticals Facts for prescribers (Fakta för förskrivare)
  11. ^ a b c d e f g h i j k l m n o Flockhart DA (2007). "Drug Interactions: Cytochrome P450 Drug Interaction Table". Indiana University School of Medicine. Retrieved on July 2011
  12. ^ Fukuda T, Imai Y, Komori M, Nakamura M, Kusunose E, Satouchi K, Kusunose M (Jan 1993). "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. PMID 8454577.
  13. ^ Fukuda T, Imai Y, Komori M, Nakamura M, Kusunose E, Satouchi K, Kusunose M (Feb 1994). "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. PMID 8206883.
  14. ^ Kölble K (Dec 1993). "Regional mapping of short tandem repeats on human chromosome 10: cytochrome P450 gene CYP2E, D10S196, D10S220, and D10S225". Genomics. 18 (3): 702–4. doi:10.1016/S0888-7543(05)80378-7. PMID 8307581.
  15. ^ Raucy, J. L.; Schultz, E. D.; Wester, M. R.; Arora, S.; Johnston, D. E.; Omdahl, J. L.; Carpenter, S. P. (1997-12-01). "Human lymphocyte cytochrome P450 2E1, a putative marker for alcohol-mediated changes in hepatic chlorzoxazone activity". Drug Metabolism and Disposition: The Biological Fate of Chemicals. 25 (12): 1429–1435. ISSN 0090-9556. PMID 9394034.
  16. ^ Desai HD, Seabolt J, Jann MW (2001). "Smoking in patients receiving psychotropic medications: a pharmacokinetic perspective". CNS Drugs. 15 (6): 469–94. doi:10.2165/00023210-200115060-00005. PMID 11524025.
  17. ^ Lieber CS (Jun 1999). "Microsomal ethanol-oxidizing system (MEOS): the first 30 years (1968-1998)--a review". Alcoholism, Clinical and Experimental Research. 23 (6): 991–1007. doi:10.1111/j.1530-0277.1999.tb04217.x. PMID 10397283.
  18. ^ Ray, D. C.; Drummond, G. B. (1991-07-01). "Halothane hepatitis". British Journal of Anaesthesia. 67 (1): 84–99. ISSN 0007-0912. PMID 1859766.
  19. ^ Nanji, A. A.; Zhao, S.; Sadrzadeh, S. M.; Dannenberg, A. J.; Tahan, S. R.; Waxman, D. J. (1994-10-01). "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): 1280–1285. ISSN 0145-6008. PMID 7847620.
  20. ^ Koide, Cheryl L.K.; Collier, Abby C.; Berry, Marla J.; Panee, Jun (2011-01-07). "The effect of bamboo extract on hepatic biotransforming enzymes – Findings from an obese–diabetic mouse model". Journal of ethnopharmacology. 133 (1): 37–45. doi:10.1016/j.jep.2010.08.062. ISSN 0378-8741. PMC 3471658. PMID 20832461.
  21. ^ Johansson, I.; Ekström, G.; Scholte, B.; Puzycki, D.; Jörnvall, H.; Ingelman-Sundberg, M. (1988-03-22). "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): 1925–1934. ISSN 0006-2960. PMID 3378038.
  22. ^ Raucy, J. L.; Lasker, J. M.; Kraner, J. C.; Salazar, D. E.; Lieber, C. S.; Corcoran, G. B. (1991-03-01). "Induction of cytochrome P450IIE1 in the obese overfed rat". Molecular Pharmacology. 39 (3): 275–280. ISSN 0026-895X. PMID 2005876.
  23. ^ Kitam, Volodymyr O.; Maksymchuk, Oksana V.; Chashchyn, Mykola O. (2012-12-17). "The possible mechanisms of CYP2E1 interactions with HSP90 and the influence of ethanol on them". BMC Structural Biology. 12 (1): 1–7. doi:10.1186/1472-6807-12-33. ISSN 1472-6807. PMC 3544703. PMID 23241420.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  24. ^ Doty SL, James CA, Moore AL, Vajzovic A, Singleton GL, Ma C, Khan Z, Xin G, Kang JW, Park JY, Meilan R, Strauss SH, Wilkerson J, Farin F, Strand SE (Oct 2007). "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. Bibcode:2007PNAS..10416816D. doi:10.1073/pnas.0703276104. PMC 2040402. PMID 17940038.

Further reading

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  • Smith G, Stubbins MJ, Harries LW, Wolf CR (Dec 1998). "Molecular genetics of the human cytochrome P450 monooxygenase superfamily". Xenobiotica; The Fate of Foreign Compounds in Biological Systems. 28 (12): 1129–65. doi:10.1080/004982598238868. PMID 9890157.
  • Kessova I, Cederbaum AI (Sep 2003). "CYP2E1: biochemistry, toxicology, regulation and function in ethanol-induced liver injury". Current Molecular Medicine. 3 (6): 509–18. doi:10.2174/1566524033479609. PMID 14527082.
  • Webb A, Lind PA, Kalmijn J, Feiler HS, Smith TL, Schuckit MA, Wilhelmsen K (Jan 2011). "The investigation into CYP2E1 in relation to the level of response to alcohol through a combination of linkage and association analysis". Alcoholism, Clinical and Experimental Research. 35 (1): 10–8. doi:10.1111/j.1530-0277.2010.01317.x. PMID 20958328.


Category:Cytochrome P450 Category:EC 1.14.13

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