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Investigations into the Mode of Action of the Cocarcinogen 12-O-Tetradecanoyl-phorbol-13-acetate Using Auxotrophic Bacteria

Department of Pharmaceutics, School of Pharmacy, University of Bath, Claverton Down, Claverton Down, Bath BA2 7AY [C. J. S.], and Department of Parmacognosy, The School of Pharmacy, University of London, 29-39, Brunswick Square, London W.C1N 1AX, United Kingdom

Auxotrophic strains of Salmonella typhimurium with single-base substitution and frame-shift mutations to histidine dependence have been used to investigate the action of the cocarcinogen 12-O-tetradecanoyl-phorbol-13-acetate (TPA). This chemical exhibited no mutagenic or toxic effects on the bacterial test strains. TPA (1 µg/ml) was shown to have no effect on the reduction in cell viability produced by the chemical mutagens N-methyl-N¹-nitro-N-nitrosoguanidine and 4-nitroquinoline 1-oxide, but the frequency of reversion to histidine independence induced by these mutagens was increased by factors of 3 and 5.5, respectively. Enhancement of chemically induced mutagenesis was also observed in auxotrophic strains of S. typhimurium lacking excision repair, but the extent of the enhancement was reduced, the enhancement ratios being 2 and 3.2 for N-methyl-N¹-nitro-N-nitrosoguanidine and 4-nitroquinoline 1-oxide, respectively. Phorbol, the parent diterpene of TPA, is not cocarcinogenic and showed no enhancement of chemically induced mutagenesis in any of the test strains. The observation that TPA is most effective in enhancing mutagenesis in strains with competent excision repair could suggest that the cocarcinogen may act on this repair system, with the consequence that increased numbers of residual or unrepaired mutagen-induced lesions remain in the DNA. However, experiments measuring recovery from ultraviolet-induced damage in the test strains failed to show any inhibition or reduction in efficiency in the excision repair system when TPA was present.

Received 6/ 6/76. Accepted 4/29/77.