Skip to main content
SpringerLink
Log in

Distribution of soluble epoxide hydrolase, cytochrome P450 2C8, 2C9 and 2J2 in human malignant neoplasms

  • Original Paper
  • Published:
Journal of Molecular Histology Aims and scope Submit manuscript

Summary

Soluble epoxide hydrolase (sEH) is a bifunctional enzyme with a C-terminal epoxide hydrolase activity and an N-terminal phosphatase activity. Arachidonic acid epoxides, previously suggested to be involved in apoptosis, oncogenesis and cell proliferation, are generated by cytochrome P450 epoxygenases and are good substrates of the sEH C-terminal domain. In addition, the N-terminal phosphatase domain hydrolyzes isoprenoid mono- and pyrophosphates, which are involved in cell signaling and apoptosis. Here we provide a comprehensive analysis of the distribution of sEH, CYP2C8, 2C9 and 2J2 in human neoplastic tissues using tissue micro-arrays. The human neoplastic tissue micro-arrays provide a well-controlled side by side analysis of a wide array of neoplastic tissues and their surrounding normal tissue controls. Many of the neoplastic tissues showed altered expression of these enzymes as compared to normal tissues. Altered expression was not limited to the neoplastic tissues but also found in the surrounding non-neoplastic tissues. For example, sEH expression in renal and hepatic malignant neoplasms and surrounding non-neoplastic tissues was found to be significantly decreased, whereas expression was found to be increased in seminoma as compared to normal tissues. Our study warrants further investigation of the role of altered expression of these enzymes in neoplastic tissues.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Burke YD, Stark MJ, Roach SL, Sen SE, Crowell PL (1997) Inhibition of pancreatic cancer growth by the dietary isoprenoids farnesol and geraniol. Lipids 32:151–156

    PubMed  CAS  Google Scholar 

  • Capdevila JH, Falck JR, Harris RC (2000) Cytochrome P450 and arachidonic acid bioactivation. Molecular and functional properties of the arachidonate monooxygenase. J Lipid Res 41:163–181

    PubMed  CAS  Google Scholar 

  • Chan AT, Tranah GJ, Giovannucci EL, Hunter DJ, Fuchs CS (2004) A prospective study of genetic polymorphisms in the cytochrome P-450 2C9 enzyme and the risk for distal colorectal adenoma. Clin Gastroenterol Hepatol 2:704–712

    Article  PubMed  CAS  Google Scholar 

  • Chang TK, Weber GF, Crespi CL, Waxman DJ (1993) Differential activation of cyclophosphamide and ifosphamide by cytochromes P-450 2B and 3A in human liver microsomes. Cancer Res 53:5629–5637

    PubMed  CAS  Google Scholar 

  • Cronin A, Mowbray S, Durk H, Homburg S, Fleming I, Fisslthaler B, Oesch F, Arand M (2003) The N-terminal domain of mammalian soluble epoxide hydrolase is a phosphatase. Proc Natl Acad Sci USA 100:1552–1557

    Article  PubMed  CAS  Google Scholar 

  • Dai D, Zeldin DC, Blaisdell JA, Chanas B, Coulter SJ, Ghanayem BI, Goldstein JA (2001) Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid. Pharmacogenetics 11:597–607

    Article  PubMed  CAS  Google Scholar 

  • Draper AJ, Hammock BD (2000) Identification of CYP2C9 as a human liver microsomal linoleic acid epoxygenase. Arch Biochem Biophys 376:199–205

    Article  PubMed  CAS  Google Scholar 

  • DuTeaux SB, Newman JW, Morisseau C, Fairbairn EA, Jelks K, Hammock BD, Miller MG (2004) Epoxide hydrolases in the rat epididymis: possible roles in xenobiotic and endogenous fatty acid metabolism. Toxicol Sci 78:187–195

    Article  PubMed  CAS  Google Scholar 

  • Dy GK, Bruzek LM, Croghan GA, Mandrekar S, Erlichman C, Peethambaram P, Pitot HC, Hanson LJ, Reid JM, Furth A, Cheng S, Martell RE, Kaufmann SH, Adjei AA (2005) A phase I trial of the novel farnesyl protein transferase inhibitor, BMS-214662, in combination with paclitaxel and carboplatin in patients with advanced cancer. Clin Cancer Res 11:1877–1883

    Article  PubMed  CAS  Google Scholar 

  • Edwards PA, Ericsson J (1999) Sterols and isoprenoids: signaling molecules derived from the cholesterol biosynthetic pathway. Annu Rev Biochem 68:157–185

    Article  PubMed  CAS  Google Scholar 

  • Enayetallah AE, Grant DF (2006) Effects of human soluble epoxide hydrolase polymorphisms on isoprenoid phosphate hydrolysis. Biochem Biophys Res Commun 341:254–260

    Article  PubMed  CAS  Google Scholar 

  • Enayetallah AE, French RA, Thibodeau MS, Grant DF (2004) Distribution of soluble epoxide hydrolase and of cytochrome P450 2C8, 2C9, and 2J2 in human tissues. J Histochem Cytochem 52:447–454

    PubMed  CAS  Google Scholar 

  • Hammock BD, Ota K (1983) Differential induction of cytosolic epoxide hydrolase, microsomal epoxide hydrolase, and glutathione S-transferase activities. Toxicol Appl Pharmacol 71:254–265

    Article  PubMed  CAS  Google Scholar 

  • Imig JD, Zhao X, Capdevila JH, Morisseau C, Hammock BD (2002) Soluble epoxide hydrolase inhibition lowers arterial blood pressure in angiotensin II hypertension. Hypertension 39:690–694

    Article  PubMed  CAS  Google Scholar 

  • Jiang JH, Jia WH, Qin HD, Liang H, Pan ZG, Zeng YX (2004) Expression of cytochrome P450 enzymes in human nasopharyngeal carcinoma and non-cancerous nasopharynx tissue. Ai Zheng 23:672–677

    PubMed  CAS  Google Scholar 

  • Jiang JG, Chen CL, Card JW, Yang S, Chen JX, Fu XN, Ning YG, Xiao X, Zeldin DC, Wang DW (2005) Cytochrome P450 2J2 promotes the neoplastic phenotype of carcinoma cells and is up-regulated in human tumors. Cancer Res 65:4707–4715

    Article  PubMed  CAS  Google Scholar 

  • Jung O, Brandes RP, Kim IH, Schweda F, Schmidt R, Hammock BD, Busse R, Fleming I (2005) Soluble epoxide hydrolase is a main effector of angiotensin II-induced hypertension. Hypertension 45:759–765

    Article  PubMed  CAS  Google Scholar 

  • Komatsu T, Yamazaki H, Shimada N, Nakajima M, Yokoi T (2000) Roles of cytochromes P450 1A2, 2A6, and 2C8 in 5-fluorouracil formation from tegafur, an anticancer prodrug, in human liver microsomes. Drug Metab Dispos 28:1457–1463

    PubMed  CAS  Google Scholar 

  • Komatsu T, Yamazaki H, Shimada N, Nagayama S, Kawaguchi Y, Nakajima M, Yokoi T (2001) Involvement of microsomal cytochrome P450 and cytosolic thymidine phosphorylase in 5-fluorouracil formation from tegafur in human liver. Clin Cancer Res 7:675–681

    PubMed  CAS  Google Scholar 

  • Kozak W, Aronoff DM, Boutaud O, Kozak A (2003) 11,12-epoxyeicosatrienoic acid attenuates synthesis of prostaglandin E2 in rat monocytes stimulated with lipopolysaccharide. Exp Biol Med (Maywood) 228:786–794

    CAS  Google Scholar 

  • Kroetz DL, Zeldin DC (2002) Cytochrome P450 pathways of arachidonic acid metabolism. Curr Opin Lipidol 13:273–283

    Article  PubMed  CAS  Google Scholar 

  • Lapple F, von Richter O, Fromm MF, Richter T, Thon KP, Wisser H, Griese EU, Eichelbaum M, Kivisto KT (2003) Differential expression and function of CYP2C isoforms in human intestine and liver. Pharmacogenetics 13:565–575

    Article  PubMed  Google Scholar 

  • Lara PN Jr, Law LY, Wright JJ, Frankel P, Twardowski P, Lenz HJ, Lau DH, Kawaguchi T, Gumerlock PH, Doroshow JH, Gandara DR (2005) Intermittent dosing of the farnesyl transferase inhibitor tipifarnib (R115777) in advanced malignant solid tumors: a phase I California Cancer Consortium Trial. Anticancer Drugs 16:317–321

    Article  PubMed  CAS  Google Scholar 

  • London SJ, Daly AK, Leathart JB, Navidi WC, Idle JR (1996) Lung cancer risk in relation to the CYP2C9*1/CYP2C9*2 genetic polymorphism among African-Americans and Caucasians in Los Angeles County, California. Pharmacogenetics 6:527–533

    Article  PubMed  CAS  Google Scholar 

  • London SJ, Sullivan-Klose T, Daly AK, Idle JR (1997) Lung cancer risk in relation to the CYP2C9 genetic polymorphism among Caucasians in Los Angeles County. Pharmacogenetics 7:401–404

    Article  PubMed  CAS  Google Scholar 

  • Maier TJ, Schilling K, Schmidt R, Geisslinger G, Grosch S (2004) Cyclooxygenase-2 (COX-2)-dependent and -independent anticarcinogenic effects of celecoxib in human colon carcinoma cells. Biochem Pharmacol 67:1469–1478

    Article  PubMed  CAS  Google Scholar 

  • Michaelis UR, Fisslthaler B, Medhora M, Harder D, Fleming I, Busse R (2003) Cytochrome P450 2C9-derived epoxyeicosatrienoic acids induce angiogenesis via cross-talk with the epidermal growth factor receptor (EGFR). Faseb J 17:770–772

    PubMed  CAS  Google Scholar 

  • Moghaddam MF, Motoba K, Borhan B, Pinot F, Hammock BD (1996) Novel metabolic pathways for linoleic and arachidonic acid metabolism. Biochem Biophys Acta 1290:327–339

    PubMed  Google Scholar 

  • Moghaddam MF, Grant DF, Cheek JM, Greene JF, Hammock BD (1997) Bioactivation of leukotoxins to their toxic diols by epoxide hyrolase. Nat Med 3:562–566

    Article  PubMed  CAS  Google Scholar 

  • Newman JW, Morisseau C, Harris TR, Hammock BD (2003) The soluble epoxide hydrolase encoded by EPXH2 is a bifunctional enzyme with novel lipid phosphate phosphatase activity. Proc Natl Acad Sci USA 100:1558–1563

    Article  PubMed  CAS  Google Scholar 

  • Node K, Huo Y, Ruan X, Yang B, Spiecker M, Ley K, Zeldin DC, Liao JK (1999) Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. Science 285:1276–1279

    Article  PubMed  CAS  Google Scholar 

  • Pacifici GM, Temellini A, Giuliani L, Rane A, Thomas H, Oesch F (1988) Cytosolic epoxide hydrolase in humans: development and tissue distribution. Arch Toxicol 62:254–257

    Article  PubMed  CAS  Google Scholar 

  • Peri KG, Varma DR, Chemtob S (1997) Stimulation of prostaglandin G/H synthase-2 expression by arachidonic acid monoxygenase product, 14,15-epoxyeicosatrienoic acid. FEBS Lett 416:269–272

    Article  PubMed  CAS  Google Scholar 

  • Przybyla-Zawislak BD, Srivastava PK, Vazquez-Matias J, Mohrenweiser HW, Maxwell JE, Hammock BD, Bradbury JA, Enayetallah AE, Zeldin DC, Grant DF (2003) Polymorphisms in human soluble epoxide hydrolase. Mol Pharmacol 64:482–490

    Article  PubMed  CAS  Google Scholar 

  • Rooney PH, Telfer C, McFadyen MC, Melvin WT, Murray GI (2004) The role of cytochrome P450 in cytotoxic bioactivation: future therapeutic directions. Curr Cancer Drug Targets 4:257–265

    Article  PubMed  CAS  Google Scholar 

  • Roques M, Bagrel D, Magdalou J, Siest G (1991) Expression of arylhydrocarbon hydroxylase, epoxide hydrolases, glutathione S-transferase and UDP-glucuronosyltransferases in H5–6 hepatoma cells. Gen Pharmacol 22:677–684

    PubMed  CAS  Google Scholar 

  • Schmelzer KR, Kubala L, Newman JW, Kim IH, Eiserich JP, Hammock BD (2005) Soluble epoxide hydrolase is a therapeutic target for acute inflammation. Proc Natl Acad Sci USA 102:9772–9777

    Article  PubMed  CAS  Google Scholar 

  • Sinal CJ, Miyata M, Tohkin M, Nagata K, Bend JR, Gonzalez FJ (2000) Targeted disruption of soluble epoxide hydrolase reveals a role in blood pressure regulation. J Biol Chem 275:40504–40510

    Article  PubMed  CAS  Google Scholar 

  • Sinicrope FA, Gill S (2004) Role of cyclooxygenase-2 in colorectal cancer. Cancer Metastasis Rev 23:63–75

    Article  PubMed  CAS  Google Scholar 

  • Wang Z, Chen HT, Roa W, Finlay W (2003) Farnesol for aerosol inhalation: nebulization and activity against human lung cancer cells. J Pharm Pharm Sci 6:95–100

    PubMed  Google Scholar 

  • Wixtrom RN, Hammock BD (1985) Membrane-bound and soluble-fraction epoxide hydrolases; methodological aspects. In: Zakim D, Vessey DA (eds) Methodological aspects of drug metabolizing enzymes. Wiley, London, pp 1–93

    Google Scholar 

  • Wu S, Moomaw CR, Tomer KB, Falck JR, Zeldin DC (1996) Molecular cloning and expression of CYP2J2, a human cytochrome P450 arachidonic acid epoxygenase highly expressed in heart. J Biol Chem 271:3460–3468

    Article  PubMed  CAS  Google Scholar 

  • Yang MD, Wu CC, Chiou SH, Chiu CF, Lin TY, Chiang IP, Chow KC (2003) Reduction of dihydrodiol dehydrogenase expression in resected hepatocellular carcinoma. Oncol Rep 10:271–276

    PubMed  CAS  Google Scholar 

  • Yu Z, Xu F, Huse LM, Morisseau C, Draper AJ, Newman JW, Parker C, Graham L, Engler MM, Hammock BD, Zeldin DC, Kroetz DL (2000) Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids. Circ Res 87:992–998

    PubMed  CAS  Google Scholar 

  • Zeldin DC (2001) Epoxygenase pathways of arachidonic acid metabolism. J Biol Chem 276:36059–36062

    Article  PubMed  CAS  Google Scholar 

  • Zeldin DC, Wei S, Falck JR, Hammock BD, Snapper JR, Capdevila JH (1995) Metabolism of epoxyeicosatrienoic acids by cytosolic epoxide hydrolase: substrate structural determinants of asymmetric catalysis. Arch Biochem Biophys 316:443–451

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Dr. B. Hammock (University of California, Davis) for providing the polyclonal anti-human soluble epoxide hydrolase rabbit serum, and to Dr. D. Zeldin (Laboratory of Pulmonary Pathobiology, NIEHS, National Institutes of Health) for providing the polyclonal anti-human CYP2J2 rabbit serum. We also thank Ione Jackman and Lynn Howlett (Histology laboratory, University of Connecticut) for their advice and assistance during the completion of this work. Supported by Boehringer Ingelheim 2005–2006 fellowship and NIH Grants ES011630 and GM56708.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Storrs, CT, 06269, USA

    Ahmed E. Enayetallah & David F. Grant

  2. Department of Pathobiology and Veterinary Science, University of Connecticut, Storrs, CT, 06269, USA

    Richard A. French

Authors
  1. Ahmed E. Enayetallah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard A. French
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David F. Grant
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David F. Grant.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Enayetallah, A.E., French, R.A. & Grant, D.F. Distribution of soluble epoxide hydrolase, cytochrome P450 2C8, 2C9 and 2J2 in human malignant neoplasms. J Mol Hist 37, 133–141 (2006). https://doi.org/10.1007/s10735-006-9050-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10735-006-9050-9

Keywords

Search

Navigation