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Mutagenic and Cell-transforming Activities of Triol-Epoxides as Compared to Other Chrysene Metabolites¹

Department of Toxicology of the University, Obere Zahlbacher Straße 67, D-6500 Mainz, Federal Republic of Germany [H. G., A. S., W. B., F. O.], Department of Toxicology of the University, D-2000 Hamburg, Federal Republic of Germany [H. M., H. M.], and Chester Beatty Laboratories, Fulham Road, London, SW3 6JB, England [R. M. H., P. L. G.]

The syn- and anti-isomers of the bay-region diol-epoxides of chrysene and of 3-hydroxychrysene and their metabolic precursors have been investigated for mutagenicity in Salmonella typhimurium (reversion to histidine prototrophy) and V79 Chinese hamster cells (acquirement of resistance to 6-thioguanine) and for transforming activity in M2 mouse prostate cells. Other known and potential chrysene metabolites have been included in mutagenicity experiments. Direct mutagenic activity in S. typhimurium TA 100 exhibited, in order of potency, anti-triol-epoxide > syn-triol-epoxide > anti-diol-epoxide > syn-diol-epoxide > chrysene 5,6-oxide >> chrysene-1,2-quinone, chrysene-3,4-quinone, and chrysene 5,6-quinone. Chrysene, the six isomeric chrysenols, and the trans-dihydrodiols [trans-1,2-dihydroxy-1,2-dihydrochrysene (chrysene-1,2-diol), trans-3,4-dihydroxy-3,4-dihydrochrysene, trans-5,6-dihydroxy-5,6-dihydrochrysene, and 9-hydroxy-trans-1,2-dihydroxy-1,2-dihydrochrysene (9-hydroxychrysene-1,2-diol)] were inactive per se but were activated to mutagens in the presence of reduced nicotinamide adenine dinucleotide phosphate-fortified postmitochondrial fraction (S9 mix) of liver homogenate from Arochlor 1254-treated rats. Chrysene, 3-hydroxychrysene, chrysene-1,2-diol, and 9-hydroxychrysene-1,2-diol were activated efficiently; the other compounds were activated weakly. In S. typhimurium TA 98, the mutagenic activities of the chrysene derivatives were weak in comparison with those in the strain TA 100. trans-3,4-Dihydroxy-3,4-dihydrochrysene (in the presence of S9 mix) was the most efficacious mutagen in strain TA 98. The relative mutagenic potencies of the directly active compounds differed from the results obtained in strain TA 100, in that in strain TA 98 the anti-diol-epoxide was more mutagenic than the triol-epoxides and chrysene 5,6-oxide was more mutagenic than syn-diol-epoxide and syn-triol-epoxide. In V79 cells, the order of mutagenic potency was: anti-triol-epoxide > anti-diol-epoxide > syn-triol-epoxide > syn-diol-epoxide > chrysene 5,6-oxide > chrysene-1,2-diol (in the presence of S9 mix) > 9-hydroxychrysene-1,2-diol (in the presence of S9 mix) > trans-3,4-dihydroxy-3,4-dihydrochrysene in the presence of S9 mix). Chrysene, 3-hydroxychrysene, 5-hydroxychrysene, and 6-hydroxychrysene showed no mutagenic effects in V79 cells, either in the presence or absence of S9 mix. In the cell transformation experiments, chrysene and 3-hydroxychrysene gave negative results, chrysene-1,2-diol, 9-hydroxychrysene-1,2-diol, the syn-diol-epoxide and the syn-triol-epoxide were weakly active, the anti-diol-epoxide was moderately active, and the anti-triol-epoxide was the chrysene derivative with the highest transforming activity; furthermore, the anti-triol-epoxide was the most cytotoxic compound in bacteria and in mammalian cells, usually followed by the anti-diol-epoxide. 4-Hydroxychrysene in S. typhimurium and 5-hydroxychrysene in V79 cells were strongly cytotoxic.

It is concluded that while the diol-epoxides and triol-epoxides are not the only biologically active chrysene metabolites, their mutagenic and cell-transforming activities are much higher than those of the other chrysene derivatives examined. The syn-diastereomers were consistently less active than the anti-isomers. The presence of the phenolic hydroxyl group in the 9-position potentiated the biological activities and also enhanced chemical reactivity, as indicated by the half-lives of the compounds in buffer (determined from mutagenic activities in S. typhimurium). Together with data on the DNA adducts present in mouse skin treated with chrysene, the mutagenicity and cell-transformation results presented provide strong evidence that 9-hydroxy-r-1,t-2-dihydroxy-t-3,4-oxy-1,2,3,4-tetrahydrochrysene is a significant ultimately carcinogenic metabolite of chrysene.

¹ This work was supported by the Deutsche Forschungsgemeinschaft (SFB 302) and by grants to the Chester Beatty Research Institute, Institute of Cancer Research, the Royal Cancer Hospital of the Medical Research Council, and the Cancer Research Campaign.

² To whom requests for reprints should be addressed.

Received 3/11/86. Revised 5/22/86. Accepted 5/28/86.