Relevance of plasmid pKM101-mediated mutagenicity in bacteria to genotoxicity in mammalian cells.

Abstract

Three structurally related compounds, 4-acetoxy-3-acetoxy-methyl-acetophenone (AAMAP), 1-[4'-hydroxy-3'-hydroxy-methylphenyl]-2-[benzyl-t-butylamino] ethanone hydrochloride (HHBEH) and 1-[4'-hydroxy-3'-hydroxymethyl-phenyl]-2-[benzyl-t-butylamino] ethanol (HHBE), gave positive dose-related mutagenic responses in the Ames test when Salmonella typhimurium strain TA100 was used as the test organism. Strain TA100 carries the hisG46 allele, which is revertable by base changes, together with plasmid pKM101, which encodes mucAB genes that are analogous to umuDC, the chromosomal SOS-repair genes of Escherichia coli K-12. None of the compounds was mutagenic in Ames strain TA1535, which is the plasmid-free derivative of strain TA100. Only AAMAP, and that at only the highest concentration tested, was mutagenic in strain TA98, which detects frameshift mutations and carries plasmid pKM101. No compound was significantly mutagenic in strain TA1538, which is the plasmid-free derivative of strain TA98. When the three compounds were tested for the induction of sister-chromatid exchanges (SCEs) in Chinese hamster cells, the two more potent mutagens, AAMAP and HHBEH were found to increase SCEs, whereas HHBE did not give a significant response at any concentration tested. Ames test data showing plasmid pK101-dependent mutagenesis are therefore, at least for these compounds, relevant indicators of eukaryotic genotoxicity.