Abstract
Inhibition of gap junctional intercellular communication (GJIC) is a predictive short term test for tumor promoting activity. A new metabolic cooperation assay has been developed, which takes the cytochrome P-450 metabolism into account. In this assay the inhibitory activity of tobacco smoke condensates (CSC) and CSC fractions from high and low tar cigarettes was tested. CSC of both high and low tar cigarettes and fractions thereof contained tumor promoting activity. The tar yield of the cigarettes did not closely reflect the effects in the GJIC assay and the major constituent nicotine had no effect. The effect was only marginally greater in cells expressing different cytochrome P-450 enzymes, indicating that the active substances are not metabolized by these enzymes. The activities of CSC fractions were considerably lower than the activities in the unfractionated CSC. This may indicate that compounds in the CSC act strongly synergistically. Furthermore, CSC and CSC fractions synergistically inhibit GJIC with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate, indicating different mechanisms of action.
References
Aylsworth CF, Trosko JE, Chang C-C, Benjamin K, Lockwood E (1989) Synergistic inhibition of metabolic cooperation by oleic acid or 12-O-tetradecanoylphorbol-13-acetate and dichlorodiphenyltrichloroethane in Chinese hamster cells: implications of a role for protein kinase C in the regulation of gap junctional intercellular communication. Cell Biol Toxicol 5: 27–37
Budunova IV, Williams GM (1994) Cell culture assays for chemicals with tumor-promoting or tumor-inhibiting activity based on the modulation of intercellular communication. Cell Biol Toxicol 10: 71–116
Curvall M, Enzell CR, Jansson T, Petterson B, Thelestam M (1984) Evaluation of the biological activity of cigarette-smoke condensate fractions using six in vitro short-term tests. J Toxicol Environ Health 14: 163–180
Davidson JS, Baumgarten IM, Harley EH (1985) Inhibition of intercellular junctional communication in human fibroblasts by triphenylmethane, triphenylmethylchloride, tetraphenylboron and related compounds. Biochim Biophys Acta 847: 1–7
Dogra S, Doehmer J, Glatt H, Mölders H, Siegert P, Friedberg T, Seidel A, Oesch F (1990) Stable expression of rat cytochrome P-450IA1 cDNA in V79 Chinese hamster cells and their use in mutagenicity testing. Mol Pharmacol 37: 608–613
Feron VJ, Griesemer RA, Nesnow S et al. (1986) Testing of complex chemical mixtures. In: Montesano R, Bartsch H, Vainio H et al. (eds) Long-term and short-term assays for carcinogens: a critical appraisal. IARC, Lyon, pp 483–494
Flodström S, Wärngård L, Hemming H, Fransson R, Ahlborg UG (1988) Tumour promotion related effects by the cyclodiene insecticide endosulfan studied in vitro and in vivo. Pharmacol Toxicol 62: 230–235
Fujiki H, Suganuma M, Nakayasu M, Tahira T, Endo Y, Shudo K, Sugimura T (1984) Structure-activity studies on synthetic analogues (indolactams) of the tumor promoter teleocidin. Gann 75: 866–870
Hagiwara N, Irie K, Tokuda H, Koshomizu K (1987) The metabolism of indole alkaloid tumor promoter, (−)-indolactam V, which has the fundamental structure of teleocidins, by rat liver microsomes. Carcinogenesis 8: 963–965
Hartman TG, Rosen JD (1983) Inhibition of metabolic cooperation by cigarette smoke condensate and its fractions in V-79 Chinese hamster lung fibroblasts. Proc Natl Acad Sci USA 80: 5305–5309
Heussen GA (1991) Inhibition of intercellular communication by airborne particulate matter. Arch Toxicol 65: 252–256
Heussen GA, Alink GM (1992) Inhibition of gap-junctional intercellular communication by TPA and airborne particulate matter in primary cultures of rat aveolar type II cells. Carcinogenesis 13: 719–722
IARC (1986) Evaluation of the carcinogenic risk of chemicals to humans, tobacco smoking, volume 38. IARC Monographs, International Agency for Research on Cancer, Lyon
Jone C, Erickson LM, Trosko JE, Netzloff ML, Chang C-C (1985) Inhibition of metabolic cooperation by the anticonvulsants, diphenylhydantoin and phenobarbital. Teratogen Carcinogen Mutagen 5: 379–391
Klaunig JE, Ruch RJ (1990) Role of inhibition of intercellular communication in carcinogenesis. Lab Invest 62: 135–145
Kobayashi N, Hoffmann D, Wynder EL (1974) A study of tobacco carcinogenesis. Epithelial changes induced in the upper respiratory tracts of Syrian golden hamsters. J Natl Cancer Inst 53: 1085–1089
Malcolm AR, Mills LJ, McKenna EJ (1985) Effects of phorbol myristate acetate, phorbol dibutyrate, ethanol, dimethylsulfoxide, phenol, and seven metabolites of phenol on metabolic cooperation between Chinese hamster V79 lung fibroblasts. Cell Biol Toxicol 1: 269–283
McKarns SC, Doolittle DJ (1991) A quantitative approach to assessing intercellular communication: studies on cigarette smoke condensates. Toxicol Appl Pharmacol 111: 58–68
Mills LJ, Robson DL, Malcolm AR (1991) Interactive effects of aldrin, cyclohexylamine, 2,4-diaminotoluene and two phorbol esters on metabolic cooperation between V79 cells. Carcinogenesis 12: 1293–1299
Rutten AAJJL, Jongen WMF, de Haan LHJ, Hendriksen EGJ, Koeman JH (1988) Effect of retinol and cigarette-smoke condensate on dye-coupled intercellular communication between hamster tracheal epithelial cells. Carcinogenesis 9: 315–320
Takahashi M, Imaida K, Mitsumori K, Okamiya H, Shinoda K, Yoshimura H, Furukawa F, Hayashi Y (1992) Promoting effects of cigarette smoke on the respiratory tract carcinogenesis of Syrian golden hamsters treated with diethylnitrosamine. Carcinogenesis 13: 569–572
Thelestam M, Curvall M, Enzell CR (1980) Effect of tobbaco smoke compounds on the plasma membrane of cultured human lung fibroblasts. Toxicology 15: 203–217
Toraason M, Bohrman JS, Elmore E, Wyatt G, McGregor D, Willington SE, Zajac W (1991) Inhibition of intercellular communication in Chinese hamster V79 cells by fractionated asphalt fume condensates. J Toxicol Environ Health 34: 95–102
Trosko JE, Chang C-C (1987) Nongenotoxic mechanisms in carcinogenesis: role of inhibited intercellular communication. In: Banbury report 31: carcinogen risk assessment: new directions in the qualitative and quantitative aspects. Cold Spring Habor Laboratory, pp 139–170
Tuominen RK, McMillian MK, Ye H, Stachowiak MK, Hudson PM, Hong JS (1992) Long-term activation of protein kinase C by nicotine in bovine adrenal chromaffin cells. J Neurochem 58: 1652–1658
Van der Zandt PTJ, De Feijter AW, Homan EC, Spaaij C, de Haan LHJ, Van Aelst AC, Jongen WMF (1990) Effects of cigarette smoke condensate and 12-O-tetradecanoylphorbol-13-acetate on gap junction structure and function on cultured cells. Carcinogenesis 11: 883–888
Van Duuren BL, Sivak A, Segal A, Orris L, Langseth L (1966) The tumor-promoting agents of tobacco leaf and tobacco smoke condensate. J Natl Cancer Inst 37: 519–526
Vang O (1994) Inhibition of intercellular communication — A valuable in-vitro test for tumor promotion. Pharmacol Toxicol 74 [Suppl. 2]: 32
Vang O, Wallin H, Doehmer J, Autrup H (1993) Cytochrome P450 mediated metabolism of tumor promoters modifies the inhibition of intercellular communication: a modified assay for tumor promotion. Carcinogenesis 14: 2365–2371
Wey HE, Breitenstein MJ, Toraason M (1992) Inhibition of intercellular communication in human keratinocytes by fractionated asphalt fume condensates. Carcinogenesis 13: 1047–1050
Zamora PO, Gregory RE, Brooks AL (1983) In vitro evaluation of the tumor-promoting potential of diesel-exhaust particle extracts. J Toxicol Environ Health 11: 187–197
Zwijsen RML, de Haan LHJ, Oosting JS, Pekelharing HL, Koeman JH (1990) Inhibition of intercellular communication in smooth muscle cells of humans and rats by low density lipoprotein, cigarette smoke condensate and TPA. Atherosclerosis 85: 71–80
Author information
Authors and Affiliations
Additional information
Supported by a fellowship of Danish Research Academy and Occupational Health Foundation. A Medical Research Council statistical adviser helped in the preparation of the statistical analysis
Supported by Danish Cancer Society
Rights and permissions
About this article
Cite this article
Vang, O., Wallin, H. & Autrup, H. Inhibition of intercellular communication by condensates of high and low tar cigarettes. Arch Toxicol 69, 415–420 (1995). https://doi.org/10.1007/s002040050193
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s002040050193