7-Methylbenz[c]acridine: mutagenicity of some of its metabolites and derivatives, and the identification of trans-7-methylbenz[c]-acridine-3,4-dihydrodiol as a microsomal metabolite.

The presence of the proposed proximate carcinogen, trans-3,4-dihydro-3,4-dihydroxy-7-methylbenz[c]acridine (7MBAC-3,4-DHD) among the liver microsomal metabolites of 7-methylbenz[c]acridine (7MBAC) has been demonstrated using gas chromatography mass spectrometry (GCMS) and by co-chromatography with synthetic standards on reverse and normal phase h.p.l.c. 7MBAC-3,4-DHD represented 2.2-3.4% of the total ethyl acetate-extractable metabolites formed from 7MBAC by liver microsomes prepared from untreated and induced rats. About 2.3-2.7% of metabolites formed by lung microsomes was identified as 7MBAC-3,4-DHD. Mutagenicity studies with 7MBAC-3,4-DHD have been carried out in bacterial and mammalian systems using S9 fractions derived from rats pre-treated with Aroclor and guinea pigs pre-treated with 3-methylcholanthrene. Comparative data with other 7MBAC derivatives are also reported. The 7MBAC-3,4-DHD and the analogous dihydro derivative of 7MBAC were the most potent mutagens of those compounds requiring metabolic activation. The data imply that the 3,4-dihydrodiol is metabolised to a bay region diol epoxide as the ultimate carcinogen. In support of this anti-1,2-epoxy-trans-3,4-dihydroxy-7-methyl-1,2,3,4- tetrahydrobenz[c]acridine was a potent mutagen in the Ames and V79 cell systems without activation. The syn-isomer was less active.