Large differences in metabolic activation and inactivation of chemically closely related compounds: effects of pure enzymes and enzyme induction on the mutagenicity of the twelve monomethylated benz[a]anthracenes, 7,12-dimethylbenz[a]anthracene and benz[a]anthracenes in the Ames test

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Abstract
The twelve isomeric monomethylbenz[a]anthracenes 7,12-dimethylbenz[a]anthracene and benz[a]anthracene show a wide range of carcinogenicities from apparently inactive to very potent. In the present study, these compounds were investigated for mutagenicity with Samonella typhimurium TA 100 using postmitochondrial liver fraction from control mice or mice treated with different enzyme inducers and an NADPH-generating system (S-9 mix) for metabolic activation. Also, the effect of two enzymes, epoxide hydrolase and dihydrodiol dehydrogenase which were purified to apparent homogeneity from the microsomal and cytosolic fraction, respectively, upon the activation was studied. All 14 compounds were mutagenic, the potency at optimal conditions varying from 3 to 35 revertants per nmol. Some of the compounds were readily activated by preparations from control animals, whilst with others a marked activation was only found with preparations from treated animals. All compounds were readily activated by S-9 mix from Aroclor-1254-treated mice. With some compounds, a similarly clear effect was obtained by pretreatment with 3-methylcholanthrene, whereas phenobarbital pretreatment did not significantly improve the activation. With other compounds the reverse was the case. Addition of pure epoxide hydrolase did not affect the mutagenicity of 7,12-dimethylbenz[a]anthracene. It increased the mutagenicity of 5- and 6-methylbenz[a]anthracene, which carry the methyl group at the K-region, 2- and 3-fold, respectively. The mutagenicity of the eleven other compounds was reduced 16–94%. Dihydrodiol dehydrogenase decreased the mutagenicity of the 3 strong carcinogens 7-methylbenz[a]anthracene, 12-methylbenz[a]anthracene and 7,12-dimethylbenz[a]anthracene by 15 – 41%. With the other compounds, the effects were weaker and not statistically significant. Thus, in spite of similar chemical structures and physicochemical properties, the mutagenicity of the benz[a]anthracenes investigated in the mammalian enzyme-mediated Salmonella test is affected very differently by the same modifications of the metabolizing system. The relative mutagenic potencies, therefore, strongly depend on the system. None of the different activating systems used in the mammalian enzymemediated Salmonella test gave a good quantitative correlation of mutagenicity with carcinogenicity.

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