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Mutagenesis Advance Access published online on April 20, 2005
Mutagenesis, doi:10.1093/mutage/gei029
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© The Author 2005. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received September 20, 2004
Revised February 24, 2005
Accepted March 22, 2005

Original article

Salmonella/human S9 mutagenicity test: a collaborative study with 58 compounds

Atsushi Hakura 1*, Hiroyasu Shimada 2, Madoka Nakajima 3, Hajime Sui 4, Sachiko Kitamoto 5, Satoshi Suzuki 6, and Tetsuo Satoh 6

1 Drug Safety Research Laboratories, Eisai Co., Ltd, 1 Takehaya-machi, Kawashima-cho, Hashima-gun, Gifu 501-6195, Japan
2 Drug Safety Research Laboratory, Daiichi Pharmaceutical Co., Ltd, 16-13 Kita-Kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan
3 Biosafety Research Center, Foods, Drugs and Pesticides, 582-2 Shioshinden, Fukude-cho, Iwata-gun, Shizuoka 437-1213, Japan
4 Food and Drug Safety Center, 729-5 Ochiai, Hadano, Kanagawa 257-8523, Japan
5 Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd, 3-1-98 Kasugadenaka, Konohana-ku, Osaka 554-8558, Japan
6 HAB Biomedical Research Institute, Cornea Center Building, Ichikawa General Hospital, 5-11-13 Sugano, Ichikawa, Chiba 272-8513, Japan

* To whom correspondence should be addressed.
Atsushi Hakura, E-mail: a-hakura{at}hhc.eisai.co.jp


  Abstract

A large and extensive body of data on the use of human liver S9 fractions in the Salmonella mutagenicity test (Ames test) is presented; the data were obtained from a collaborative study by JEMS/BMS (Bacterial Mutagenicity Test Study Group) members and the Human and Animal Bridging Research Organization (HAB). In this study, the mutagenicity of 58 chemicals, many of which were judged to be human carcinogens by the IARC, was determined by the Ames test (the pre-incubation method at 37°C for 20 min) in the presence of a selected human liver S9 fraction with a high drug-metabolic activity or a pooled human liver S9 fraction with a moderate drug-metabolic activity. For reference, mutagenicity was also examined in the presence of a phenobarbital/5,6-benzoflavone-pretreated rat liver S9 fraction, which is normally used in mutagenicity testing systems. The bacterial test strains consisted of Salmonella typhimurium TA100, TA98 or YG7108. The data indicated that the mutagenicity of chemicals in the rat and human liver S9 fractions varied considerably, depending on the chemicals in question. In addition, a large inter-individual diversity in the mutagenic response to mutagens, depending on the chemical structures of the mutagens, was also demonstrated using two selected human S9 fractions. Most of the mutagens tested in this study (75%; 36 out of 48 compounds that were judged to be mutagenic in at least one S9 fraction) were less mutagenic in the presence of the two human S9 fractions than in the presence of the rat S9 fraction. On the other hand, the other compounds (25%), including some aromatic amines and nitrosamines, showed a more potent mutagenicity in the presence of either one of the two human S9 fractions than in the presence of the rat S9 fraction. These data strongly suggest that the use of human liver S9 fraction in mutagenicity testing systems may be useful for a better understanding of the mutagenic effects of chemicals on humans.


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