WORLD HEALTH ORGANIZATION ' Ю INTERNATIONAL AGENCY FOR RESEARCH ON CANCER RELEVANCE OF N-NITROSO COMPOUNDS TO HUMAN CANCER: EXPOSURES AND MECHANISMS Proceedings of the IXth International Symposium on N-Nitroso Compounds, held in Baden, Austria, 1-5 SeptemЬеr 1986 Co-sponsored by: National Cancer Institute (USA) Dr M. Okada Giapan) and associated Japanese industrial sponsors Thermedics Inc. (USA) Ciba-Geigy (Switzerland) Imperial Chemical Industries (UK) EDITORS H. BARTSCH, T.K. 0 NЕILL & R. SCHULTE-HERMANN JAR SCIENTIFIC PUBLICATIONS NO. 84 INTERNATIONAL AGENCY FOR RESEARCH ON CANCER LYON 1987 CONTENTS Foreword.................................................................. 1 Introduction................................................................ 3 Overview................................................................... 5 Keynote address P.N. Magee ............................................................. 11 1. MOLECULAR AND BIOCHEMICAL MECHANISMS Biochemical events in nitrosamine-induced hepatocarcinogenesis: relevance of animal data to human carcinogenesis R.Schulte-Hermann .....................................................17 Biochemical and molecular effects of N-nitroso compounds in human cultured cells: an overview C.C. Harris .............................................................20 Activation of the human c-Ha-ras-1 proto-oncogene by in-vitro reaction with N-nitroso- methyl(acetoxymethyl)amine S. Hirani-Hojatti, J.R. Milligan & M.C. Archer ..............................26 Specificity of OЬ-alkylguanine-DNA alkyltransferase А.E. Pegg, D. 5сicсhitaпo, K. Morimoto & M.E. Dolan .......................30 Diet- and age-dependent modulation of O6-methylguanine-DNA methyltransferase levels in mouse tissues M. Klaudc & A. von der Decker ....... .....................................35 0-Alkyl deoxythyrnidines are recognized by DNA polymerase I as deoxythymidine or deoxycytidinc В. Singer, S.J. Spengler, F. Chavez, J. Sagi, J.T. Kusmierek, B.D. Preston & L.A. Loeb ............................................................37 Repair of synthetic oligonucleotides containing OЬ-methylguanine, O6-ethylguаnine and 04-methylthymiпe, by O6-alkylguanine-DNA alkyltransferase R.J. Graves, S.F.L. Li & P.F. Swann .......................................41 Synthesis and structural studies by nuclear magnetic resonance of dodecadeoxynucleotides containing OЬ-methylguanine, OЬ-еthylguапin arid 0'-methylthymine B.F.L. Li, P.F. Swann, M. Kalnik & D.J. Patel ..............................44 Organ specificity, metabolism and reaction with DNA of aliphatic nitrosomethyl- alkylamines P. Kleihues, E. von Hole, I. Schmerold, L.K. Keefer & W. Lijinsky .............49 Immunocytochemical studies on the formation and repair of O6-аlkylguaniпe in rat tissues E. Scherer, A.A.J. Jenner & L. Den Engelse .................................55 Molecular dosimetry of DNA alkylation during chronic exposure to carcinogens • J.A. Swenberg, J.A. Boucheron, F.H. Deal, F.C. Richardson & L.A. Tyeryar.....59 Long-term persistence of nitrosamine-induced structural damage to heterochromatic DNA B.W. 5tewart & E.J. Ward .............. o .................................64 N-Nitroso-N-methylaniline; possible mode of DNA modification S.R. Koepke, M.B. Kroeger-Koepke & C.J. Michejda .........................68 /3-Oxidized N-nitrosoalkylcarbamates as models for DNA alkylation by N-nitrosobis- (2-охорторуl)amine in Syrian hamsters D.L. Nagel, R. Lewis, M. Fischer, K. Stansbury, К. Ѕtерап & T.A. Lawson . .71 2. METABOLISM Recent findings on the metabolism of Р-hydroxyalkylпitrоsаmines С.J. Michejda, S.R. Koepke, M.B. Kroeger-Koepke & W. Bosan ...............77 In-vivo activation of N-nitrosodiethanolamine and other N-nitroso-2-hуdroxyalkуlamiпes by alcohol dehydrogenase and sulfotransferase E. Denkel, W. Sterzel & G. Eisenbrand ................................... ...83 Metabolism and cellular interactions of N-nitrosodiethanolamine J.G. Farrelly, B.J. Thomas & W. Lijinsky ...................................87 13-Oxidation of N-nitrosodiеthanolamine in different animal species in vitro and in vivo M. Bonfanti, C. Magagnotti, R. Fanelli & L. Airoldi ..........................91 o-Nitrosaminoaldehydes: highly reactive metabolites R.N. Loeppky, W. Tomasik, G. Eisenbrand & E. Denkel ......................94 Directly-acting mutagens formed from N-nitroso-N-(formylmethyl)alkylamines E. Suzuki, M. Osabe, M. Mochizuki & M. Okada ...........................100 Enzymatic mechanisms in the metabolic activation 0f N-nitrosodialkylamines C.S. Yang, C. Patten, M.J. Lee, M. Li, J.S.H. Yoo, J. Pan & J. Hong ..........104 Mechanism and control of denitrosation of N-nitrosodimethylamine H.-J. Haussmann & J. Werringloer ........................................109 Potential for metabolic deactivation of carcinogenic N-nitrosodimethylamine in vivo L.K. Keefer, T. Anjo, Y.-H. Heur, C.S. Yang & B.A. Mico .................... 113 Same aspects of cytochrome P450-dependent denitrosation of N-nitrosamines K.E. Appel, M. Schоеpkе, T. Scheрer, S. Gdrsdorf, M. Bauszus, C.S. Ruhl, R. Kramer, H.H. Ruf, B. Sрiegelhaldеr, M. Wiessler & A.G. Hildebrandt .................117 Kinetic isotope effect on the demethylation and denitrosation of N-nitrosodimctliylamine in vitro C.S. Yang, D. Wade, T. Anjo & L.K. Keefer ................................124 Structure-activity relationships in metabolism and mutagenicities of N-nitrosamines J.B. Guttenplan .........................................................129 The pig as an animal model for the study of nitrosamine metabolism G.W. Harrington, P.N. Magee, H.M. Pylypiw, Jr, R.F. Bevi11, D.R. Nelson & J.C. Thurmon ..........................................................132 The ferret as a model for endogenous synthesis and metabolism of N-nitrosamines J.S. Wishnok, S.R. Tannenbaum, J.G. Fox, J.E. Mesina & L.C. Hotahng.......135 Cell type-specific differences in metabolic activation of N-nitrosodiethylamine by human lung cancer cell lines H.M. Schuller, M. Falzon, A.F. Gazdar & T. Hegedus .......................138 A comparative study of the mutagenic activation of carcinogenic N-nitrosopropylamines by various animal species aid man Y. Mori, H. Yamazaki & Y. Konishi .......................................141 Metabolism of the oesophageal carcinogen N-nitrosomethylamylamine: changes with age, clearance from blood and DNA alkylation S.S. Mirvish, C. Ji, M. Makary, H.A.J. Schut & C. Krokos ...................144 Exhalation of N-nitrosoethylvinylamine after application of N-nitrosodicthylamine to Sprague-Dawley rats R.G. Klein, B. Schmezer, Р. Schmezer & B. 5piegelhalder .................... 148 Investigation into the pharmacodynamics of the carcinogen N-nitrodimethylamine M. Hassel, E. Frei, H.R. 5cherf & M. Wiessler ........ .................... 150 Urinary metabolites of N-nitrosodibutylamine in the rat: identification of N-acetyl-S-butyl- L-cysteine derivatives E. Suzuki, M. Osabe, M. Okada, T. Ishizaka & T. Suzuki ....................153 Extrahepatic microsomal metabolism of N-nitrosodi-n-butylamine in rats E. Richter, J. Schulze & W. Zwickenpflug ..................................156 Experimental model for investigating bladder carcinogen metabolism using the isolated rat urinary bladder L. Airoldi, M. Bor►fanti, C. Magagnotti & R. Fanelli ......................... 159 Could N-nitrosamino phosphates be transport forms of activated N-nitrosamines? N. Frank, M. Wiessler, B.L. Pool & E. Frei .................................162 Chemical and mutagenic properties of a-phosphonooxynitrosamines M. Mochizuki, A. lkarashi, A. Suzuki, N. Sekiguchi, Т. Anjo & M. Okada...... 165 aг-Glucuroпides of N-nitrosomethylbenzyla.mine M. Wiessler & G. Rossnagcl ..............................................170 Effect of ascorbic acid on the metabolism of N-nitrosopiperidine M. Nakamura, Y. Osada, Y. Horiguchi, T. Nakaoka, K. Ito & T. Kawabata .....173 Effect of (+)-catechin, dimethyl sulfoxide and ethanol on the microsome-mediated metabolism of two hepatocarcinogens. N-nitrosodimethylamine and aflatoxin B, H.R. Prasanna, P.D. Lotlikar, N. Hacobian, L.L. Ho & P.N. Magee ...........175 Effect of dietary selenium on biotransformation and excretion of mutagenic metabolites of N-nitrosodimethylamine and 1,1-dimethylhydrazine in the liver perfusion cell culture system B. Beije, U. Olsson & A. (unfelt ...........................................178 Different effects of chemicals on metabolism of N nitrosamines in rat liver T. Kawanishi, Y. Ohno, A. Takahashi, A. Takanaka & Y. Iron. ..............181 Effect of butylated hydroxyanisole on the metabolism of N-nitrosodi-n-butylamine and N-nitrosobutyl(4-hydroxybutyl)amine by rat hepatic S9 preparations in vitro R. Рastorelli, A. Ancidei, R. Fanelli & L. Airoldi ............................183 3. REACTION WITH MACROMOLECULES Formation and fate of nucleic acid and protein adducts derived from N-uitroso-bile acid conjugates D.E.G. Shuker, J.R. Howell & B.W. Street .................................187 A method to determine the carbamoylating potential of 1-(2-chloroethyl)-I-nitrosoureas W. Stahl, R.L. Krauth-Siegel, R.H. Schirmer & G. Eiscnbrand ................191 Alkylation of 2'-deoxythymidylyl-(3'л5)-2'-deoxythymidine with 2-hydroxyethylпitroso- итеа and stability of the resulting phosphotriester N. 1011er, J. Conrad & G. Eisenbrand ...............................:.....194 Mechanism of inhibition of N-methyl-N-nitrosourea-induced mutagenicity and DNA binding by ellagic acid R. Dixit & B. Gold ......................................................197