K-region
aziridines of
polycyclic aromatic hydrocarbons reverted Salmonella typhimurium his- (TA100, TA98) and Escherichia coli trp- strains (WP2 uvrA), without requiring activation by mammalian
enzymes. The number of revertants induced per nmol in S. typhimurium TA 100, the most responsive strain, variea from 6 to 10,000 for the seven monoaziridines and the two bisaziridines tested. Interestingly, the mutagenic potencies (y) of the monoaziridines were closely related (r = 0.984) with those of the corresponding
epoxide analogues (x) by the equation y = 19.6 X0.97, i.e., the
aziridines were about 20-fold stronger
mutagens than were the
epoxides. One of the
aziridines,
benzo(a)pyrene (BP)-4,5-imine, was investigated in several additional mutagenicity test systems: toxicity in
DNA repair-deficient (rec-) and -proficient (rec+) Bacillus subtilis strains; induction of
6-thioguanine resistance in V79 Chinese hamster cells; and induction of sister chromatid exchanges in cultured human fibroblasts. In all systems, BP-4,5-imine was much more active than the
epoxide analogue, BP-4,5-oxide. The difference in activity was particularly large in the two test systems with mammalian target cells in which several hundredfold higher concentrations of the
epoxide had to be used in order to elicit equipotent effects. Even r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydro-BP, which is one of the most potent
mutagens known for V79 cells, was less active in the mammalian cells than was BP-4,5-imine. One reason that arene
imines are such potent
mutagens may be that they are poorly detoxified. Addition of highly purified
microsomal epoxide hydrolase, which strongly reduced the mutagenicity of BP-4,5-oxide and benz(a)anthracene-5,6-oxide in S. typhimurium, had no effect on the mutagenicity of the corresponding
aziridines. Furthermore, while benz(a)anthracene-5,6-oxide was inactivated by highly purified cytosolic
epoxide hydrolase, benz(a)anthracene-5,6-imine was not inactivated. It is noteworthy that the arene
imines are isomeric with and structurally closely related to aromatic
amines. Some
aziridines derived from nonaromatic structures (
ethylene imines) have been reported as metabolites of
xenobiotics; others are used as chemotherapeutics. At present, however, the results are mainly of theoretical interest in that a new type of arene derivatives with exceptionally potent, probably ultimate, mutagenicity was discovered and may be exploited for the study of mechanisms of chemical
carcinogenesis.