The inhibition by naphthoquinones and anthraquinones of 2-amino-3-methylimidazo[4,5- f ]quinoline metabolic activation to a mutagen: a structure-activity relationship study

Abstract

Nine naphthoquinones, 19 anthraquinones, and nine structurally related monoketonic compounds such as anthrone, xanthone, etc., inhibited mutagenicity induced by 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in Salmonella typhimurium TA 98 in the presence of rat liver S9 with distinct structure-activity relationships. A carbonyl function was a prerequisite for antimutagenicity while, in general, anthraquinones (IC50 values: 2.3–>213 nmol/ml top agar) were more potent antimutagens than structurally related monoketonic compounds (IC50 values: 25.3–94.9 nmol/ml top agar) and naphthoquinones (IC50 values: 3.7–90.7 nmol/ml top agar). The parent compounds and methyl substituted derivatives were already the most potent while introduction of polar substituents such as COOH and SO3H considerably reduced antimutagenicity. Introduction of OH functions had equivocal effects: with increasing numbers, antimutagenic potencies were concomitantly reduced; however, anthraflavic acid, chrysazin, quinizarin, and especially 5,8-dihydroxy-1,4-naphthoquinone were more potent than the parent compounds. The patterns of inhibition by quinones of 7-ethoxyresorufin-O-dealkylase activities in rat liver microsomes, linked to cytochrome P-450-dependent oxidation of IQ to N-hydroxy-IQ (N-OH-IQ), were in general identical with those obtained in the Salmonella/reversion assay except for chrysophanic acid, emodin, and some naphthoquinones which were very potent in this assay (IC50: 0.20–45.0 μM). On the other hand, mutagenicity of N-OH-IQ in S. typhimurium TA 98NR was not inhibited by nonpolar quinones (except 1,4-naphthoquinone) but rather by polar compounds and especially by hydroxyquinones (IC50 values: 5.3–106.7 nmol/ml top agar or not reached). Inhibition of mutagenic activities of IQ, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, 2-amino-6-methyldipyrido[1,2-a:3′,2′-d]imidazole, and 3-amino-1-methyl-5H-pyrido[4,3-b]indole by chrysazin, chrysophanic acid, physicon, and purpurin varied, but no clearcut structure-activity relationships of the mutagens were observed.