Abstract
The alpha1-agonist phenylephrine (5 μM) induces an increase in the free cytosolic Ca2+ concentration, followed by repetitive transients of the cytoplasmic Ca2+ concentration, in single Fura-2 loaded hepatocytes. The tumor promoting, hypolipidemic drug nafenopin suppressed the cellular Ca2+ response to phenylephrine. The effect of nafenopin on the Ca2+ increase and Ca2+ oscillations was largely prevented by the specific protein kinase C inhibitor Gö 6976. This finding suggests involvement of protein kinase C in the action of nafenopin on phenylephrine induced Ca2+ mobilization.
References
Barritt GJ, Hughes BP (1991) The nature and mechanism of activation of the hepatocyte receptor-activated Ca2+ inflow system. Cell Signalling 3: 283–292
Berridge MJ (1993) Inositol triphosphate and calcium signalling. Nature 361: 315–325
Bieri F, Muakkassah-Kelly S, Waechter F, Sagelsdorf P, Sträubli W, Bentley P (1990) The significance of in vitro studies on peroxisome proliferation. Toxicol in Vitro 4: 428–431
Bouvier M, Leeb-Lundberg LMF, Benovic JL, Caron MG, Lefkowitz RJ (1987) Regulation of adreneric receptor function by phosphorylation. J Biol Chem 262: 3106–3113
Bronfman M, Orellana A, Morales F, Stäubli W, Bentley P (1989) Potentiation of diacylglycerol-activated protein kinase C by acyl-coenzyme A thioesters of hypolipidemic drugs. Biochem Biophys Res Commun 159: 1026–1031
Bronfman M, Morales MN, Amigo L, Orellana A, Nunez L, Cardenas L, Hidalgo PC (1992) Hypolipidaemic drugs are activated to acyl-CoA esters in isolated rat hepatocytes. Biochem J 284: 289–295
Cattley RC, Popp JA (1989) Differences between the promoting activities of the peroxisome proliferator Wy-14,643 and phenobarbital in rat liver. Cancer Res 49: 3246–3251
Clemens MJ, Trayner I, Menaya J (1992) The role of protein kinase C isoenzymes in the regulation of cell proliferation and differentiation. J Cell Sci 103: 881–887
Corvera S, Schwarz KR, Graham RM, Garvia-Sainz JA (1986) Phorbol esters inhibit α1-adrenergic effects and decrease the affinity of liver cell α1-adrenergic receptors for (−)-epinephrine. J Biol Chem 261: 520–526
Exton JH (1988) Role of phosphoinositides in regulation of liver function. Hepatology 8: 152–166
Gibson GG, Orton TC, Tamburini PP (1982) Cytochrome P450 induotion by clofibrate. Purification and properties of a hepatic cytochrome P450 relatively specific for the 12- and 11-hydroxylation of dodecanoic acid (lauric acid). Biochem J 203: 161–168
Green S (1992) Nuclear receptors and chemical carcinogenesis. Trends Pharmacol Sci 13: 251–255
Grynkitwicz G, Poenie M, Tsien R (1985) A new generation of Ca2+-indicators with greatly improved fluorescence properties. J Biol Chem 260: 3440–3450
Issemann I, Green S (1990) Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347: 645–650
Kawanishi T, Blank LM, Harootunian AT, Smith MT, Tsien RY (1989) Ca2+ oscillations induced by harmonal stimulation of individual Fura-2-loaded hepatocytes. J Biol Chem 264: 12859–12866
Keller BJ, Bradford BU, Marsman DS, Cattley RC, Popp JA, Bojes HK, Thurman RG (1993) The nongenotoxic hepatocarcinogen Wy-14,643 is an uncoupler of oxidative phosphorylation in vivo. Toxicol Appl Pharmacol 119: 52–58
Kleinschroth J, Hartenstein J, Rudolph C, Schächtele C (1993) Nonglycosidic/nonaminoalkyl-substituted indolocarbazoles as inhibitors of protein kinase C. Bio Med Chem Lett 3: 1959–1964
Kraupp-Grasl B, Huber W, Putz B, Gebracht U, Schulte-Hermann (1990) Tumor promotion by peroxisome proliferator nafenopin involving a specific subtype of altered foci in rat liver. Cancer Res 50: 3701–3708
Leibold E, Greim H, Schwarz LR (1994) Inhibition of intercellular communication of rat hepatocytes by nafenopin: involvement of protein kinase C. Carcinogenesis 15: 1265–1269
Lock EA, Mitchell AM, Elcombe CR (1989) Biochemical mechanisms of induction of hepatic peroxisome proliferation. Annu Rev Pharmacol Toxicol 29: 145–163
Marsman DS, Goldsworthy TL, Popp JA (1992) Contrasting hepatocytic peroxisome proliferation, lipofucsin accumulation and cell turnover for the hepatocarcinogens Wy14,643 and clofibric acid. Carcinogenesis 13: 1011–1017
Martiny-Baron G, Kazanietz MG, Mischak H, Blumberg PM, Kochs G, Hug H, Marme D, Schächtele C (1993) Selective inhibition of protein kinase C isozymes by the indolocarbazole Gö 6976. J Biol Chem 268: 9194–9197
McPhail LC, Clayton CC, Snyderman R (1984) A potential second messenger role for unsaturated fatty acids: activation of Ca2+-dependent protein kinase. Science 224: 622–624
Nishizuka Y (1988) The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature 334: 661–665
Orellana A, Hidalgo PC, Morales MN, Mezzano D, Bronfman M (1990) Palmitoyl-CoA and the acyl-CoA thioester of the carcinogenic peroxisome-proliferator ciprofibrate potentiate diacylglycerol-activated protein kinase C by decreasing the phosphatidylserine requirement of the enzyme. Eur J Biochem 190: 57–61
Orellana A, Holuigue L, Hidalgo PC, Faundez V, Gonzalez A, Bronfman M (1993) Ciprofibrate, a carcinogenic peroxisome proliferator, increases the phosphorylation of epidermal-growth-factor receptor in isolated rat hepatocytes. Eur J Biochem 215: 903–906
Reddy JK, Lalwai ND (1983) Carcinogenesis by hepatic peroxisome proliferators: evaluation of risk of hypolipidemic drugs and industrial plasticizers to humans. Crit Rev Toxicol 12: 1–58
Rooney AT, Sass EJ, Thomas AP (1989) Characterization of cytosolic calcium oscillations induced by phenylephrine and vasopressin in single Fura-2-loaded hepatocytes. J Biol Chem 264: 17131–17141
Sanchez-Bueno A, Cobbold PH (1992) Effect of perturbing diacylglycerol metabolism on cytosolic free Ca2+ oscillations induced in single hepatocytes. FEBS Lett 312: 57–60
Sanchez-Bueno A, Dixon CJ, Woods NM, Cuthbertson KSR, Cobbold PH (1990) Inhibitors of protein kinase C prolong the falling phase of each free-calcium transient in a hormone-stimulated hepatocyte. Biochem J 268: 627–632
Stampfl A (1994) Measurement of the intracellular free calcium in single heart cells by means of Fura-2: Influence of extracellular magnesium. In: Golf S, Dralle D, Vechiet L (eds) Magnesium 1993. John Libbey, London Paris Rome, pp 45–47
Striggow F, Bohnensack R (1993) Verapamil and dilthiazem inhibit receptor-operated calcium channels and intracellular calcium oscillations in rat hepatocytes. FEBS Lett 318: 341–344
Woods NM, Cuthbertson KSR, Cobbold PH (1986) Repetitive transient rises in cytoplasmic free calcium in hormone-stimulated hepatocytes. Nature 319: 600–602
Woods NM, Cuthbertson KSR, Cobbold PH (1987) Phorbol-ester induced alterations of free calcium ion transients in single rat hepatocytes. Biochem J 246: 619–623
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Leibold, E., Stampfl, A. & Schwarz, L.R. Suppression of agonist induced Ca2+ oscillations in cultured hepatocytes by nafenopin: possible involvement of protein kinase C. Arch Toxicol 70, 252–255 (1996). https://doi.org/10.1007/s002040050269
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s002040050269