Skip to main content

Advertisement

SpringerLink
Log in

Alpha1-and beta2-adrenoceptors in the human liver with mass-forming intrahepatic cholangiocarcinoma: density and coupling to adenylate cyclase and phospholipase C

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Besides the regulation of hepatic metabolic pathways in which adrenoceptors are mainly involved, their effect on the second messenger cAMP is thought to be related to the growth and differentiation of neoplastic cells. However, few studies have been done on the status of these structures in the human liver affected by cholangiocarcinoma (CC). Thus, in this study, changes in densities of α1- and β2-adrenoceptors (α1-and β2-ARs) were investigated in membranes of human liver with cholangiocarcinoma, and for comparison, in membranes of non-adjacent non-tumour liver using the potent antagonists [3H]-prazosin and [1I]-iodocyanopindolol (ICYP) respectively. In addition, the activity of membrane-bound phospholipase C (PLC) and adenylate cyclase (AC) was also studied. In CC liver, the density of α1-and β2-ARs was significantly reduced, compared with non-tumour liver tissues (α1-ARs: 23.38±4.69 vs 80.35±10.52, P=0.0002 β2-ARs: 14.27±2.93 vs 33.22±4.32 fmol/mg protein, P=0.03), whereas the ligand affinities (KD) remained unchanged. The β2-selective antagonist ICI 118,551 was about 100 times more potent in inhibiting ICYP binding than the β1-selective antagonist CGP 20712A; thus, more than 98% of the β-ARs were of the β2-subtypes. The AC activity upon stimulants acting on β-AR (isoprenaline), G-protein (GTP, NaF) and AC (forskolin) was decreased in CC liver. Similarly, noradrenaline-stimulated PLC activity was significantly reduced in tumour tissues. In conclusion, in CC liver the α1- and β2-ARs density was down-regulated and the neoplastic invasion blunted AC and PLC activity. These quantitative changes may help to elucidate not fully understood pathogenetic mechanisms of disturbed hepatic metabolic processes, such as hypoglycemia during cancer in human liver.

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
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Abraham G, Kottke C, Dhein S, Ungemach FR (2003). Pharmacological and biochemical characterization of the beta-adrenergic signal transduction pathway in different segments of the respiratory tract. Biochem Pharmacol 66:1067–1081

    Article  PubMed  CAS  Google Scholar 

  • Benchekroun LE, Couton D, Postic C et al. (2005). Overexpression of β2-adrenergic receptors in mouse liver alters the expression of glyconeogenic and glycolytic enzymes. AJP-Endocrinol Metab 288:E715–E722

    Article  CAS  Google Scholar 

  • Bevilacqua M, Norbiato G, Chebat E et al (1991). Changes in alpha-1 and beta-2 adrenoceptor density in human hepatocellular carcinoma. Cancer 67:2543–2551

    Article  PubMed  CAS  Google Scholar 

  • Bilski AJ, Halliday SE, Fitzgerald (1983). The pharmacology of a beta 2-selective adrenoceptor antagonist (ICI 118,551). J Cardiovasc Pharmacol 5:430–437

    Article  PubMed  CAS  Google Scholar 

  • Brodde OE (1991). Beta1 and beta2-adrenoceptors in the human heart: properties, function, and alterations in chronic heart failure. Pharmacol Rev 43:203–242

    PubMed  CAS  Google Scholar 

  • Cho-Chung YS (1988). Models of tumour regression in endocrine-related cancer. In: Stoll BA(ed). Endocrine management of cancer. Biological Bases. Karger, Basel, pp 1–13

    Google Scholar 

  • Daza JF, Parrilla R, Martin-Requro A (1997). Influence of thyroid status on hepatic alpha 1-adrenoceptor responsiveness. Am J Physiol 273:E1065–E1072

    PubMed  CAS  Google Scholar 

  • De Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM (1999). Biliary tract cancers. N Engl J Med 341:1368–1378

    Article  PubMed  Google Scholar 

  • Dennis JW, Laferte S (1985). Recognition of asparagine-linked oligosaccharides on murine tumour cells by natural killer cells. Cancer Res 6034–6040

  • Dooley DJ, Bittiger H, Reymann NC (1986). CGP 20712 A: a useful tool for quantitating beta 1-and beta 2-adrenoceptors. Eur J Pharmacol 130:137–139

    Article  PubMed  CAS  Google Scholar 

  • Draoui A, Vandewalle B, Hornez L, Revillion F, Lefebvre J (1991). β-adrenergic receptors in human breast cancer: identification, Characterization and Correlation with progestron and estradiol receptors. Anticancer Res 11:677–680

    PubMed  CAS  Google Scholar 

  • El-Rafai MF, Chan TM (1984). Evidence of heterogeneous distribution of alpha1 and beta-adrenergic binding sites on rat-liver cell surface. Biochim Biophys Acta 775:356–364

    Article  PubMed  Google Scholar 

  • Guellaen G, Yates–Aggerbeck M, Vauquelin G, Strosberg D, Hanoune J (1978). Characterization with [3H] dihydroergocryptine of the alpha-adrenergic receptor of the hepatic plasma membrane. Comparison with the beta-adrenergic receptor in normal and adrenalectomized rats. J Biol Chem 253:1114–1120

    PubMed  CAS  Google Scholar 

  • Gangopadhyay A, Lazure DA, Thomas P (1998). Adhesion of colorectal carcinoma cells to the endothelium is mediated by cytokines from CEA stimulated Kupffer cells. Clin Exp Metastasis 16:703–712

    Article  PubMed  CAS  Google Scholar 

  • Gangopadhyay A, Bajenova O, Kelly TM, Thomas P (1996). Carcinoembryonic antigen induces cytokine expression in Kupffer cells: implication for hepatic metastasis from colon cancer. Cancer Res 56:4805–4810

    PubMed  CAS  Google Scholar 

  • Garro M, Lopez M, Ruiz I, Callado LF, Meana J, Salles J (2001). Regulation of phospholipase Cβ activity by muscarinic acetylcholine and 5-HT2 receptors in crude and synaptosomal membranes from human cerebral cortex. Neuropharmacology. 40:686–695

    Article  PubMed  CAS  Google Scholar 

  • Hakomori S (1989). Aberrant glycosylation in tumours and tumour-associated carbohydrate antigens. Adv Cancer Res 52:257–331

    PubMed  CAS  Google Scholar 

  • Hemmings SJ, Wilson TR (2003). Lymphosarcoma-induced alterations in hepatic adrenergic receptors: implications to the hypoglycemia of cancer cachexia. Mol Cell Biochem 250:167–177

    Article  PubMed  CAS  Google Scholar 

  • Hoffman BB, Hu ZW (2000). Alpha-1-adrenoceptors and vascular smooth muscle cell growth. Prostate 9:29–33

    Article  CAS  Google Scholar 

  • Hoffman BB, Lefkowitz RJ (1982) Agonist interactions with alpha-adrenergic receptors. J Cardiovasc Pharmacol 4:S14–S18

    Article  PubMed  Google Scholar 

  • Hoffmann C, Leitz MR, Oberdorf-Maass S, Lohse MJ, Klotz KN (2004) Comparative pharmacology of human beta-adrenergic receptor subtypes-characterization of stably transfected receptors in CHO cells. Naunyn-Schmiedeberg’s Arch Pharmacol 365:151–159

    Article  CAS  Google Scholar 

  • Hyltander A, Drott C, Korner U, Sandstrom R, Lundholm K (1991) Elevated energy expenditure in cancer patients with solid tumours. Eur J Cancer 27:9–15

    Article  PubMed  CAS  Google Scholar 

  • Jard S, Cantau B, Jakobs KH (1981). Angiotensin II and alpha-adrenergic agonists inhibit rat liver adenylate cyclase. J Biol Chem 256:2603–2606

    PubMed  CAS  Google Scholar 

  • Katsanos KH, Kistanou M, Christodoulou DK, Tsianos EV (2002). High CA 19–9 levels in benign biliary tract diseases. Report of four cases and review of the literature. Eur J Intern Med 13:132–135

    Article  PubMed  Google Scholar 

  • Kawai Y, Powell A, Arinze IJ (1986). Adrenergic receptors in human liver plasma membranes: predominance of β2-and α1-receptor subtypes. JCE and M 62:827–832

    CAS  Google Scholar 

  • Kleene R, Berger EG (1985). The molecular and cell biology of glycosyltransferases. Biochim Biophys Acta 1154:283–325

    Google Scholar 

  • Kost DP, DeFrances MC, Lee CR, Michalopoulos GK (1992). Patterns of alpha-1-adrenergic receptor expression in regenerating and neoplastic hepatic tissue. Pathobiology 60:303–308

    Article  PubMed  CAS  Google Scholar 

  • Kunos G, Ishac EJ, Gao B, Jiang L (1995). Inverse regulation of hepatic alpha 1B-and beta 2-adrenergic receptors. Cellular mechanisms and physiological implications. Ann N Y Acad Sci 757:261–271

    Article  PubMed  CAS  Google Scholar 

  • Kuusela P, Haglund C, Roberts PJ (1991). Comparison of a new tumour marker CA 242 with CA19–9, CA50 and carcinoembryonic antigen (CEA) in digestive tract diseases. Br J Cancer 63:636–640

    PubMed  CAS  Google Scholar 

  • Kyprianou N, Chon J, Benning CM (2000). Effects of alpha-1-adrenoceptor antagonists on cell proliferation and apoptosis in the prostate: therapeutic implications in prostate disease. Prostate 9:42–46

    Article  CAS  Google Scholar 

  • Labarba RC (1970). Experimental and environmental factors in cancer. Psychosom Med 32:259–276

    PubMed  CAS  Google Scholar 

  • Langhans W (2003). Role of the liver in the control of glucose-lipid utilization and body weight. Curr Opin Clin Nutr Metab Care 6:449–455

    Article  PubMed  CAS  Google Scholar 

  • Lin J, Yan F, Hu S, Ju H (2004). Chemiluminescent immunosensor for CA 19–9 based on antigen immobilization on a cross-linked chitosan membrane. JIM 291:165–174

    Article  CAS  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL and Randall RJ (1951). Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275

    PubMed  CAS  Google Scholar 

  • Magnani JL, Steplewski Z, Koprowski H, Ginsburg V (1983). Identification of the gastrointestinal and pancreatic cancer-associated antigen detected by monoclonal antibody 19–9 in the sera of patients as a mucin. Cancer Res 43:5489–5492

    PubMed  CAS  Google Scholar 

  • Maitra SR, Wojnar MM, Lang CH (2000). Alterations in tissue glucose uptake during the hyperglycaemic and hypoglycaemic phases of sepsis. Eur J Intern Med 13:379–385

    CAS  Google Scholar 

  • Malbon CC (1980). Liver cell adenylate cyclase and β-adrenergic receptors: increased β-adrenergic receptor number and responsiveness in the hypothyroid rat. J Biol Chem 255:8692–8699

    PubMed  CAS  Google Scholar 

  • Marchetti B, Paulain M, Labrie F (1988). Castration levels of plasma testosterone have potent stimulatory effects on androgen sensitive parameters on the rat prostate. J Steroid Biochem 31:411–418

    Article  PubMed  CAS  Google Scholar 

  • Marchetti B, Coini M, Badr M, Follea N, Pelletier G (1987). Ovarian adrenergic nerves directly participate in the control of LHRH and β-adrenergic receptors during a puberty: a biochemical and autoradiographic study. Endocrinology 121:219–226

    Article  PubMed  CAS  Google Scholar 

  • Marchetti B, Spinola PG, Pelletier G, Labrie F (1991). A potential role for catecholamines in the development and progression of carcinogen-induced mammary tumours: hormonal control of β-adrenergic receptors and correlation with tumour growth. J Steroid Biochem Molec Biol 38:307–320

    Article  PubMed  CAS  Google Scholar 

  • Nagino M, Nimura Y, Kamiya J et al (1998). Segmental liver resections for hilar cholangiocarcinoma. Hepatogastroenterology 45:7–13

    PubMed  CAS  Google Scholar 

  • Nakeeb A, Pitt HA, Sohn TS et al (1996). Cholangiocarcinoma: a spectrum of intrahepatic, perihilar and distal tumours. Ann Surg 224:463–473

    Article  PubMed  CAS  Google Scholar 

  • Nicolson GL (1982). Cancer metastases. Organ colonization and the cell-surface properties of malignant cells. Biochim Biophys Acta 695:113–176

    PubMed  CAS  Google Scholar 

  • Patel T (2001). Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology 33:1353–1357

    Article  PubMed  CAS  Google Scholar 

  • Patel AH, Harnois DM, Klee GG, La Russo NF, Gores GJ (2000). The utility of CA 19–9 in the diagnosis of cholangiocarcinoma in patients without sclerosing cholangitis. Am J Gastroenterol 95:204–220

    Article  PubMed  CAS  Google Scholar 

  • Poyet P, Labrie F (1986). Characterization of β-adrenergic receptors in dispersed rat Leydig cells. J Androl 8:7–12

    Google Scholar 

  • Robinson IA, McKee G, Kissin MW (1995). Typing and grading breast carcinoma on fine needle aspiration: is this clinically useful information? Diagn Cytopathol 13:260–265

    Article  PubMed  CAS  Google Scholar 

  • Salomon Y, Londos C, Rodbell M (1974). A highly sensitive adenylate cyclase assay. Anal Biochem 58:541–548

    Article  PubMed  CAS  Google Scholar 

  • Sarsero D, Russell FD, Lynham JA, Rabnott G, Yang I, Fong KM, Li L, Kaumann AJ, Molenaar P (2003). (-)-CGP 12177 increases contractile force and hastens relaxation of human myocardial preparations through a propranolol-resistant state of the beta1-adrenoceptor. Naunyn-Schmiedeberg’s Arch Pharmacol 367:10–21

    Article  PubMed  CAS  Google Scholar 

  • Schmelck PH, Hanoune J (1980). The hepatic adrenergic receptors. Mol Cell Biochem 33:35–48

    Article  PubMed  CAS  Google Scholar 

  • Seamon KB, Daly JW (1986). Forskolin: its biological and chemical properties. Adv Cyclic Nucleotide Protein Phosphorylation Res 20:1–150

    PubMed  CAS  Google Scholar 

  • Shavit Y, Terman GW, Martin FC, Lewis JW, Liebeskind JC, Galle RP (1985). Stress, opioid peptides, the immune system and cancer. J Immun 135:834–837

    Google Scholar 

  • Snell K, Evans CA (1988). Characterization of rat liver beta-adrenoceptors during prenatal development as determined by 125I-iodopindolol radioligand binding essays. Br J Pharmacol 93:817–826

    PubMed  CAS  Google Scholar 

  • Stevens DP, Mackay IR (1973). Increased carcinoembryonic antigen in heavy cigarette smokers. Lancet 2:1238–1239

    Article  PubMed  CAS  Google Scholar 

  • Suh Y (2002). Cell signalling in aging and apoptosis. Mech Ageing Dev 23:881–890

    Article  Google Scholar 

  • Thomas AP, Renard-Rooney DC, Hajnoczky G, Rob-Gaspers LD, Lin C, Rooney TA (1995). Subcellular organization of calcium signalling in hepatocytes and the intact liver. Ciba Found Symp 188:18–49

    PubMed  CAS  Google Scholar 

  • Wolfe BB, Harden TK, Molinoff PB (1976). Beta-adrenergic receptors in rat liver: effects of adrenalectomy. Proc Natl Acad Sci U S A 73:1343–1347

    Article  PubMed  CAS  Google Scholar 

  • Wu T, Han C, Lunz JG, Michlopoulos G, Shelhamer JH, Demetris AJ (2002). Involvement of 85-kd cytosolic phospholipase A2 and cyclooxygenase-2 in the proliferation of human cholangiocarcinoma cells. Hepatology 36:363–373

    Article  PubMed  CAS  Google Scholar 

  • Yamatani K, Saito K, Takahashi K, Ohnuma H, Manaka H, Sasaki H (2001). Hormon-specific combinations of isoforms of adenylyl cyclase and phosphodiesterase in the rat liver. Regul Pept 99:45–52

    Article  PubMed  CAS  Google Scholar 

  • Zeiders JL, Seidler FJ, Slotkin TA (1999). Agonist-induced sensitization of beta-adrenoceptor signalling in neonatal rat heart: expression and catalytic activity of adenylyl cyclase. J Pharmacol Exp Ther 291:503–510

    PubMed  CAS  Google Scholar 

  • Zhou M, Yang S, Koo DJ, Ornan DA, Chaudry IH, Wang P (2001). The role of Kupffer cells α2 -adrenoceptors in norepinephrine-induced TNF-α production. Biochem et Biophys Acta 1537:49–57

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faculty of Medicine, Clinic for Visceral, Transplantation, Thoracic and Vascular Surgery, OKL, University of Leipzig, Liebig Strasse 20a, 04103, Leipzig, Germany

    W. T. Kassahun, B. Günl & J. Hauss

  2. Institute of Pathology, Faculty of Medicine, University of Leipzig, Liebig Strasse 20a, 04103, Leipzig, Germany

    A. Tannapfel

  3. Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, An den Tierkliniken 15, 04103, Leipzig, Germany

    F. R. Ungemach & G. Abraham

Authors
  1. W. T. Kassahun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B. Günl
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Tannapfel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F. R. Ungemach
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. Hauss
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G. Abraham
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to W. T. Kassahun.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kassahun, W.T., Günl, B., Tannapfel, A. et al. Alpha1-and beta2-adrenoceptors in the human liver with mass-forming intrahepatic cholangiocarcinoma: density and coupling to adenylate cyclase and phospholipase C. Naunyn Schmied Arch Pharmacol 372, 171–181 (2005). https://doi.org/10.1007/s00210-005-0017-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-005-0017-2

Keywords

Search

Navigation