Mutagenicity of glyceryl trinitrate (nitroglycerin) in Salmonella typhimurium |
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| Affiliation: | 1. Chemistry Section, Laboratory of Comparative Carcinogenesis, Frederick Cancer Research and Development Center, Frederick, MD 21702 USA;2. PRI/DynCorp, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, MD 21702, USA;3. Food and Drug Administration, Rockville, MD 20857, USA;1. Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan;2. Graduate School and Faculty of Pharmaceutical Science, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan;1. Department of Pharmacy, Zhujiang Hospital of Southern Medical University, Industrial Road No. 253, Haizhu District, Guangzhou 510282, China;2. Cultivation Base for Key Laboratory of Conservation and Utilization of Rare and Economic Species at Southeast Guangxi, Yulin Normal University, Yulin, China;3. Department of Biopharmaceutical, School of Life Science and Technology, Yulin Normal University, Yulin, China;1. Department of Entomology, Nanjing Agricultural University, Nanjing, Jiangsu 210095, China;2. Institute of Microbiology, Jiangxi Academy of Sciences, Nanchang, Jiangxi 330096, China;1. Department of Oncology, Oslo University Hospital – Norwegian Radium Hospital, Oslo, Norway;2. Department of Oncology, Akershus University Hospital, Akershus, Norway;3. Institute of Clinical Medicine, University of Oslo, Oslo, Norway;4. Department of Pathology, Oslo University Hospital – Norwegian Radium Hospital, Oslo, Norway;5. Department of Tumour Biology, Oslo University Hospital – Norwegian Radium Hospital, Oslo, Norway;6. Department of Radiology & Nuclear Medicine, Oslo University Hospital – Norwegian Radium Hospital, Oslo, Norway;7. Department of Gastroenterological Surgery, Oslo University Hospital – Norwegian Radium Hospital, Oslo, Norway |
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| Abstract: | The recent finding that the clinical nitrovasodilator, glyceryl trinitrate (GTN), is mutagenic in Salmonella typhimurium strain TA1535 has been examined in closer detail, with emphasis on its mechanism of action. GTN increased the number of His+ revertants to a maximum of 4 times over background at a GTN dose of 5 μmol/plate. Hamster liver S9 depressed the toxicity of high GTN doses and increased the maximum number of revertants to 5 times over background at 10 μmol/plate. GTN did not cause significant reversion in any of the six other S. typhimurium strains tested (TA1975, TA102, TA1538, TA100, TA100NR, YG1026), although signs of toxicity were observed. Therefore, the mutagenicity of GTN was manifest only in the repair-deficient (uvrB and lacking in pKM101) strain which is responsive to single base changes. Oligonucleotide probe hybridization of TA1535 revertants showed that virtually all of the GTN-induced mutants contained C → T transitions in either the first or second base of the hisG46 (CCC) target codon, with a preference for the latter. A similar mutational spectrum was seen previously with a complex of spermine and nitric oxide (NO) which releases nitric oxide. This suggests that NO, which can be derived from GTN via metabolic reduction, may be responsible for GTN's mutagenic action. The known NO scavenger oxymyoglobin did not substantially alter the dose response of GTN, indicating that extracellular NO was not mediating reversion. The data are consistent with the hypothesis that intracellular nitric oxide is responsible for the observed mutations. |
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