Microsomes and Drug Oxidations. Proceedings of the Third International Symposium, Berlin, July 1976

788 Pages·1977·20.475 MB·English

by  Volker Ullrich, Alfred Hildebrandt and Ivar Roots (Eds.)

MICROSOMES
AND
DRUG OXIDATIONS
Proceedings of the Third International Symposium
Berlin, July 1976
Editors
VOLKER ULLRICH IVAR ROOTS
Institute of Physiological Chemistry Institute for Clinical Pharmacology
University of the Saarland Free University of Berlin
ALFRED HILDEBRANDT RONALD W. ESTABROOK
Institute for Clinical Pharmacology South western Medical School
Free University of Berlin University of Texas
and
ALLAN H. CONNEY
Department of Biochemistry and Drug Metabolism
Roche Research Laboratories
Published as a Supplement to
BIOCHEMICAL PHARMACOLOGY
PERGAMON PRESS
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First edition 1977
Reprinted 1978
Library of Congress Cataloging in Publication Data
Symposium on Microsomes and Drug Oxidations, 3d, Berlin,
1976.
Microsomes and drug oxidations.
Includes bibliographical references.
I. Drug metabolism—Congresses. 2. Microsomes—
Congresses. 3. Oxidation, Physiological—Congresses.
4. Cytochrome P-450—Congresses. I. Ullrich, Volker.
II. Title. [DNLM: 1. Cytochrome P-450—Metabolism-
Congresses. 2. Microsomes—Metabolism—Congresses.
3. Oxidation-reduction—Congresses. 4. Drugs—Metabo-
lism—Congresses. QH603.M4 M626 1976]
RM300.S86 1976 615.7 77-3358
ISBN 0-08-021523-8
In order to make this volume available as economically and rapidly as possible the
authors' typescripts have been reproduced in their original form. This method
unfortunately has its typographical limitations but it is hoped that they in no way
distract the reader.
Printed in Great Britain by Biddies Ltd., Guildford, Surrey
LIST OF PARTICIPANTS
Achtert, Giinther, Kali-Chemie Pharma, Abt. Pharmakokinetik, D-3000 Hannover,
Hans-Bockler-Allee 20, Germany.
Agosin„ Moises, Department of Zoology, University of Georgia, Riverbend Re-
search Laboratories, Athens, Georgia 30602, USA.
Ahokas, Jorma, T., Department of Pharmacology, University of Oulu, SF-90220
Oulu 22, Finland.
Altmann, Hans-Jiirgen, Abt. Toxikologie,Max-von-Pettenkofer-Institut des Bun-
desgesundheitsamtes, Postfach, D-1000 Berlin 1+5 Germany.
5
Alvares, Alvito P., The Rockefeller University of New York, N.Y. 10021, USA.
Arvela, Pentti I., Department of Pharmacology, Free University of Berlin,
Thielallee 69/73, D-1000 Berlin 33, Germany.
Baars, A.J., Department of Pharmacology, Subfaculty Pharmacy, Sylvius Labora-
tories of the State University, Wassenaarseweg 72, Leiden, The Nether-
lands .
Von Bahr, Christer, Department of Clinical Pharmacology, Huddinge University
Hospital, S—1U186 Huddinge, Sweden.
Batt, Anne-Marie, Faculte des Sciences Pharmaceutiques et Biologiques, Labora-
toire de Biochimie Pharmacologique, 5~7, rue A. Lebrun-B.P. 1+03, F-5U001
Nancy Cedex, France.
Belvedere, Giorgio, Instituto di Ricerche Farmacologiche "Mario Negri", Via
Eritrea, 62, 1-20157 Milano, Italy.
Bend, John R., Pharmacology Branch, National Institute of Environmental
Health Sciences, P.O. Box 12233, Research Triangle Park, North Carolina
27709, USA.
Bentley, Philip, Abt. fur biochemische Pharmakologie, Pharmakologisches In-
stitut der Universitat Mainz, Obere Zahlbacher StraBe 67, D-65OO Mainz,
Germany.
Berg, Anders, KEMJ I, Karolinska Institutet, S-10U 01 Stockholm 60, Sweden.
Berggren,Margareta, Department of Forensic Medicine, Karolinska Institutet,
S-10U01 Stockholm 60, Sweden.
Beyhl, Friedrich E., Hoechst Aktiengesellschaft, Pharma Biochemie Nord D528,
D-6230 Frankfurt (M) 80, Postfach, Germany.
Bock, Karl Walter, Institut fur Toxikologie, Wilhelmstrasse 56, D-7^+00
Tubingen, Germany.
Bottcher, Irmgard, Schering AG, Miillerstr. 170-178, D-1000 Berlin 65, Germany.
xv
XVI List of Participants
Boyd, G.S., Department of Biochem., University of Edinburgh, Medical School,
Edinburgh, EH 8 9 AG, Scotland, U.K.
Breckenridge, Alasdair M., University of Liverpool, Department of Clinical
Pharmacology, New Medical Building, Ashton Street, P.O.Box 147, Liverpool,
L69 3BX, England, U.K.
Brunner, G., Med. Universitatsklinik, Humboldtallee 1, D-3400 Gottingen,Germany.
Budczies, Babette, Abt. Toxikologie, Max-von-Pettenkofer-Institut des Bundes-
gesundheitsamtes, Postfach, D-1000 Berlin 45, Germany.
Burchell, Brian, Department of Biochemistry, Medical Sciences Intitute, The
University, Dundee, DD1 4HN, Scotland, U.K.
Busch, U., Firma Dr. Karl Thomae, D-7950 Biberach/Rifi, Germany.
Capdevila, Jorge, Department of Zoology, University oi Georgia, Riverbend Re-
search Laboratories, Athens, Georgia 30602, USA.
Carlstrom, Kjell, Hormone Laboratory, Sabbatsberg Hospital, S-113 82 Stockholm,
Sweden.
Charuel, Claude, Laboratoires Pfizer, Centre de Recherches, B.P. 42, F-37400-
Amboise, France.
Cho, Arthur K., Department of Pharmacology, School of Medicine, The Center for
the Health Sciences, University of California, Los Angeles, Cal. 90024,
USA
Conney, Allan H., Hoffmann-LaRoche,Inc., Department of Biochemistry and
Metabolism, Nutley, New Jersey 07110, USA.
Coomes, Marguerite L., 809 Denton, Denton, Tx. 76201, USA.
Coon, M.J., Department of Biological Chemistry, The University of Michigan
Medical School, Ann Arbor, Michigan U8109, USA.
Cooper, David Y., 5013 Ravdin Ctyd.Bldg., Hospital of the Univ., 34th Spruce St.
Philadelphia, Pa. 19104, USA
Cox, P.J., Institute of Cancer Research, Royal Cancer Hospital, Chester Beatty
Res. Inst., Fulham Road, London SW 3 6JB, England, U.K.
Cremer-Schlede, Eva, Rudesheimer Platz 1, D-1000 Berlin 33, Germany
Davies, Donald S., Department of Clinical Pharmacology, Royal Postgraduate Me-
dical School, Ducane Road, London W12 0HS, England, U.K.
Debey, Marie-Pascale, Institute de Biologie Physico-Chimique, 13 Rue P.et M.
Curie, F-75005 Paris, France.
Denk, Helmut, A-1230 Wien, Rudolf-Zellergasse 51, Austria.
List of Participants xvi 1
Dickins, Maurice, Dept. of Drug Metabolism, Wellcome Research Laboratories,
Langley Court, Beckenham, Kent BR3 3BS, England, U.K.
Deutschmann, G., Physiologisch-chemisches Institut der Universitat des Saar-
landes, D-665O Homburg/Saar, Germany.
Diehl, Horst, Universitat Bremen, D-2800 Bremen 33, Achtergasse,Germany.
Dietsch, Agnes, Laboratoire de Biochimie Vegetale, Institut de Botanique, 28,
rue de Goethe, F-67 000 Strasbourg, France.
Down, William H., Huntingdon Research Centre, Huntingdon,Cambridgeshire PEl8
6 ES, England, U.K.
Duppel, Wilfried, Universitat des Saarlandes, Fachrichtung 3.3, Physiologische
Chemie, D-665O Homburg/Saar, Germany.
Dus, Karl M., Dept. of Biochemistry, St. Louis University School of Medicine,
1^02 South Grand Blvd., St. Louis, Missouri 6310U, USA.
Dybing, Erik, Department of Environmental Toxicology, National Institute of
Public Health, Oslo 1, Norway.
Ebel, D., University of Texas, Health Science Center at Dallas, South Western
Med. School, 5323 Harry Hines Blvd., Dallas, Texas 75235, USA.
Eben, Anneliese, Bayer AG, Institut fur Toxikologie, Friedrich-Ebert-StraBe 217,
D-56OO Wuppertal, Germany.
Elcombe, C.R., Pharmakologisches Institut der Universitat Mainz, Obere Zahl-
bacher Str. 67, D-65OO Mainz, Germany.
Ernster, Lars, Dept. of Biochem., University of Stockholm, Box 6U09, S-113-82
Stockholm, Sweden.
Estabrook, Ronald W., University of Texas, Health Science'Center at Dallas,
South Western Med. School, 5323 Harry Hines Blvd., Dallas,Texas 75235,USA.
Fann, William E., Departments of Psychiatry and Pharmacology, Baylor College of
Medicine, 1200 Moursund Ave., Houston, Texas 77025, USA.
Fauran, Francois, Laboratoires Sarget, B.P.100- Ave. du Pr. Kennedy, F-33701
Merignac, France.
Fellenius, Erik, AB Hassle, Analytical Chemistry and Biochemistry, Fack,S-^3120,
Molndal, Sweden.
Franklin, Michael, R., University of Utah, College of Pharmacy, Salt Lake City,
Utah 8M12, USA.
Garbe, Andreas, E. Merck, Institut Grafing, Am Feld 32, 8018 Grafing bei Miinchen,
Germany.
Gelboin, Harry V., National Cancer Institute, National Institute of Health, Rm.
3E 2i+, Bethesda, Maryland 20011+, USA.
XV111 List of Participants
Gielen, J., Laboratoire de Chimie Medicale, University of Liege, Bd. de la
Constitution 151, B-U020 Liege, Belgium.
Gillette, James R., Laboratory of Chemical Pharmacology, National Heart and
Lung Institute, Laboratory of Chemical Pharmacology, National Institutes
of Health, Bethesda, Maryland 2001U, USA.
Glatt, Hans R., Pharmakologisches Institut, Obere Zahlbacher Strafie 6T, D-56OO
Mainz, Germany.
Glazko, A.J., Research Laboratories, Parke, Davis & Company, 2800 Plymouth Rd.,
Ann Arbor, Michigan U8106, USA.
Golan, Mario, Wiesbadenerstr. 28 B, D-6503 Mainz-Kastel, Germany.
Grafstrom, Roland, Dept. of Forensic Medicine, Karolinska Institutet, S-10U01
Stockholm 60, Sweden.
Gram, Theodore E., Laboratory of Toxicology, National Cancer Institute NIH,
Bethesda, Md. 2001*+, USA.
Gunsalus, I.C., Department of Biochemistry, University of Illinois, Urbana, 111.
61801, USA.
Gustafsson,Jan-Xke, Department of Chemistry, Karolinska Institutet, S-10U01
Stockholm 60, Sweden.
Hanninen, Osmo, Dept. Physiology, Univ. Kuopio, P.O.Box 138, SF TO101 Kuopio 10,
Finland.
Haroz, Richard K., Battelle, Research Center,T,route de Drize, 122T - Carouge/
Geneve, Switzerland.
Heinemeyer, Gerhard, Institut fur Klinische Pharmakologie, Klinikum Steglitz,
Hindenburgdamm 30, D-1000 Berlin k5, Germany.
Herken, H. , Institut fur Pharmakologie der Frei'en Universitat Berlin, Thiel-
allee 69, D-1000 Berlin 33, Germany.
Herzberg, Mala, Ichilov Hospital, Department of Chemical Pathology, Tel Aviv,
Israel.
Herzberg, Wolfgang, Wilhelmallee h, D-2000 Hamburg 55, Germany.
Hesse, Sigrun, Gesellschaft f. Strahlen-u. Umweltforschung mbH. Miinchen, Abt.
fur Toxikologie, D-80^2 Neuherberg, Ingolstadter Landstrasse 1, Germany.
Hildebrandt, Alfred, Institut fur Klinische Pharmakologie, Klinikum Steglitz,
Hindenburgdamm 30, D-1000 Berlin U5, Germany.
Hirata, Masaharo, Department of Forensic Medicine, Karolinska Institutet,
S-10U 01 Stockholm 60, Sweden.
Hlavica, P., Pharmakologisches Institut der Universitat, D-8000 Miinchen 15,
Nufibaumstr. 26, Germany.
List of Participants xix
Hoensch, Harald, Hausserstrafie 1U0, D-7^-00 Tubingen, Germany.
Hoffbauer, R.W., Institut fur Humangenetik, MartinistraBe 52, D-2000 Hamburg 20,
Germany.
Hogberg, Johan, Rattsmedicinska Institutionen, Karolinska Institutet, S-10U 01
Stockholm 60, Sweden.
Holtzman, J.L., Clinical Pharmacology Unit, Veterans Administration Hospital
and Department of Pharmacology, University of Minnesota, Minneapolis,
Minn. 55^17, USA.
Ihlefeld, Heimbert, Universitat Bremen, Studienbereich II, D-2800 Bremen,
Achterstrasse, Germany.
Ingelman-Sundberg, Magnus, Department of Chemistry, Karolinska Institutet, Fack,
S-10U 01 Stockholm, Sweden.
Jakobsson, Sten, Dept. Forensic Medicine, Karolinska Institutet, S-10U01 Stock-
holm 60, Sweden.
Jauch, Rolf, 795 Biberach, Dr. Karl Thomae GmbH, Germany.
Jeffery, Elizabeth, Dept. Pharmacology, 105 Millard Hall, University of Minne-
sota, Minneapolis, MN 55^55, USA.
Jerina, D., Laboratory of Chemistry, National Institute of Health, Bethesda,
Md. 2001k USA.
9
Jernstrom, Bengt, Dept. of Forensic Medicin, Karolinska Institutet, S-10U01
Stockholm 60, Sweden.
Johannesen, Karin, University of Stockholm, Arrhenius Laboratory, Department of
Biochemistry, Fack, S-10U 05 Stockholm, Sweden.
Joly, Jean-Gil, Hospital St-Luc, Centre de Recherches Cliniques, 1058 St-Denis,
Montreal, Quebec, Canada H2X 3J^.
Jonen, H.G., Dept. of Pharmacology, University of Mainz, Obere Zahlbacher
Str. 67, Hochhaus, D-65OO Mainz, Germany.
Jonsson, John, University of Uppsala, Psychiatric Research Department, Uller-
§ker Hospital, 75017 Uppsala, Sweden.
Karki, Niilo, Department of Pharmacology, University of Oulu, SF-90220 Oulu 22,
Finland.
Kahl, G.F., Dept. of Pharmacology, University of Mainz, Obere Zahlbacher Str.
67, Hochhaus, D-65OO Mainz, Germany.
Kahl, Regine, Dept. of Pharmacology, University of Mainz, Obere Zahlbacher Str.
67, Hochhaus, D-65OO Mainz, Germany.
Kaminsky, Laurence, New York State Health Dept., Division of Labs, and Research,
New Scotland Ave., Albany, N.Y. 12201, USA.
xx List of Participants
Kappas, A., Rockefeller University, Dept. of Biochemistry and Drug Metabolism,
New York, N.Y. 10021, USA.
Kato, Ryuichi, 1-6, 2-Chome, Kashima, Yodogawa-ku, Osaka, 532, Japan.
Kaufmann, Rolf, Inst. fur Toxikologie, Abt. f. Zelltoxikologie, Wilhelmstrasse
56, D-T^OO Tubingen, Germany.
Kewitz, Helmut, Institut fur Klinische Pharmakologie, Klinikum Steglitz, Hin-
denburgdamm 30, D-1000 Berlin U5, Germany.
Kexel, Hugo, Lehrstuhl fur Allgem. Chemie und Biochemie der Techn. Universitat
Miinchen, D-8050 Freising-Weihenstephan, Germany.
Kiese, Manfred, Pharmakologisches Institut der Universitat Miinchen, NuBbaumstr.
26, D-8000 Miinchen 2, Germany.
Kim, Sangduk, Hels. Res. Inst., 3^20 N. Broad St., Temple Univ., Philadelphia,
Pa., USA.
Koch-Weser, Jan, Centre de Recherche Merrell, International, 16 rue d'Ankara,
6T000 Strasbourg, France.
Kremers, P., Laboratory of Chemistry, Laboratoire de Chimie Medicale,University
of Liege, Bd. de la Constitution 151, B-l+020 Liege, Belgium.
Kupfer, David, Worcester Foundation, Shrewsbury, MA. 015*+5, USA.
Larsen, John Chr., Institute of Toxicology, National Food Institute, 19 M^rkh^j
Bygade, DK-2860 S^borg, Denmark.
Lang, Matti, Dept. of Physiol., Univ. Kuopio, P.O. Box 138, SF-70101 Kuopio 10,
Finland.
Lech, John J., Dept. of Pharmacology, RM 112, Medical College of Wisconsin,
561 N 15 Th. St., Milwaukee, Wis. 53233. USA.
Lenk, Werner, Pharmakologisches Institut, NuBbaumstralBe 26, D-8000 Miinchen 2,
Germany.
Levin, Wayne, Dept. Biochemistry & Drug Metabolism, Hoffmann LaRoche Inc.,
Nutley, N.J. 07110, USA.
Lieber, Charles S., Bronx Veterans Administration Hospital, Section of Liver
Disease & Nutrition, 130 W.Kingsbridge Rd., Bronx, New York 10U68, USA.
Lind, Christina, University of Stockholm, Arrhenius Laboratory, Dept. of Bio-
chemistry, Fack, S-101+05 Stockholm, Sweden.
Lindeke, Bjorn, The Biomedical Center, University of Uppsala, Box 57^, S-75123
Uppsala, Sweden.
Lissner, R., c/o Merck, Med. Res./Medical Biochemistry, Frankfurter Str. 250,
D-6100 Darms t adt, Germany.
List of Participants xxi
Liibke, Klaus, Schering AG, Abteilung Allgemeine Biochemie, Miillerstr. 170— 178
9
D-1000 Berlin 65, Germany.
Maines, Mahin D., 283 Ashford Ave., Dobbsferry, New York 10522, USA.
Mannering, G.J., Department of Pharmacology, 105 Millard Hall, University of
Minnesota Medical School, Minneapolis, Minnesota 55^55, USA.
Marlowe, Carolyn G., Department of Pharmacology, University of Kentucky,
College of Medicine, Lexington, Kentucky U0506, USA.
Marniemi, Jukka, Department of Physiology, University of Turku, Kiinamyllynk,
10, SF-20520 Turku 52, Finland.
Marselos, Marios, Dept. of Physiology, University of Kuopio, SF-70101 Kuopio,
Finland.
Marsh, J., Physiology Department, Medical School, Observatory, Cape, Republic
of S.A.
Masters, Bettie Sue S., Department of Biochemistry, The Univ. of Texas, Health
Science Center at Dallas, 5323 Harry Hines Blvd., Dallas, Texas 75235,USA.
Mattern, Ina E. , Medical-Biological Laboratory TNO, P.O. Box 1+5, Rijswijk 2100,
The Netherlands.
Meyer, Urs A., Div. of Clinical Pharmacology, CL-25, Kantonsspital, CH-8091
Zurich, Switzerland.
Mercier, Michel, Faculte de Medecine - Ecole de Pharmacie, Tour van Helmont,
U.C.L. 73 69 Av. Emmanuel Mounier, 73, 1200 Bruxelles, Belgium.
Mieyal, John J., Department of Pharmacology, North Western University Medical
School, 303 Chicago Ave., Chicago, Illinois 60611, USA.
Mitchell, Jerry R., Laboratory of Chemical Pharmacology, National Heart and
Lung Institute, National Institutes of Health, Bethesda, Maryland 2001U,
USA.
Mohn, Gertrud, Physiologisch-Chemisches Institut der Universitat des Saarlandes,
LKH Bau hk, D-665O Homburg/Saar, Germany.
Moldeus, Peter, Dept. of Forensic Medicine, Karolinska Institutet, S-10U01
Stockholm 60, Sweden.
Moron, Maria, University of Stockholm, Arrhenius Laboratory, Department of
Biochemistry, Fack, S-10U 05 Stockholm, Sweden.
Mosser, Jacqueline, Laboratories Sarget B.B. 100 - Ave du Pr. Kennedy, F-33701
Merignac, France.
Mull, Robert, Inst. fur Biophysik und Strahlenbiologie, D-78OO Freiburg i.Br.,
Albertstr. 23, Germany.
XXI1 List of Participants
Muller-Eberhard, Ursula, Scripps Clinic & Research Foundation, Dept. of Bio-
chemistry , U76 Prospect St., La Jolla, Ca. 92037, USA.
Narasimhulu, Skakunthola, Harrison Dept. for Surgical Research, B-703, Richards
Bldg., University of Pennsylvania, Philadelphia, Pa. 1917^, USA.
Nastainczyk, Wolfgang, Physiologisch-Chemisches Institut der Universitat des
Saarlandes, D-665O Homburg/Saar, Germany.
Neal, Robert, Department of Biochemistry, Vanderbilt University School of
Medicine, Nashville, Tennessee 37232, USA.
Nebert, Daniel W., National Institute of Child Health & Human Development,
National Institutes of Health, Bethesda, Md. 2001^4, USA.
Netter, K.J., Pharmakologisches Institut der Universitat Mainz, Langenbeck-
straBe 1, D-65OO Mainz, Germany.
Noordhoek, J. , Dept. Pharmacology, Medical Faculty, Erasmus University, P.O.
Box 1738, Rotterdam, The Netherlands.
Novak, Raymond F., U00 Custer Ave., Chicago, 111. 60202, USA.
Oesch, Franz, Pharmakologisches Institut, Universitat Mainz, Obere Zahlbacher
Str. 77, D-65OO Mainz, Germany.
Okuda, Kyuichio, Physiologisch-Chemisches Institut der Universitat des Saar-
landes, D-665O Homburg/Saar, Germany.
Omura, Tsuneo, Dept. of Biology, Society of Science, Kyushu University,
Fukuoka 812, Japan.
Orrenius, Sten, Department of Forensic Medicine, Karolinska Institutet,
S-10U01 Stockholm 60, Sweden.
Orton, Terence C, Safety of Medicines Department, ICI Pharmaceuticals
Division, Mereside, Alderley Park, Macclessfield, Cheshire, England, U.K.
Paigen, Beverly, Department of Molecular Biology, Roswell Park Memorial
Institute, Buffalo, N.Y., USA.
Paigen, Kenneth, Department of Molecular Biology, Roswell Park Memorial
Institute, Buffalo, N.Y. , USA.
Parke, D.W., Dept. of Biochem., Univ. of Surrey, Guildford, Surrey GU2 5XH
England, U.K.
Pawlak, Andrzey, Dept. of Human Genetics, Medical School, Poznan 60 781,
ul. Swiecickiego 6, Poland.
Pederson, Thomas C, Department of Biochemistry, University of Illinois,
Urbana, Illinois 61801, USA.