Structure-activity relationships of anthraquinones as inhibitors of 7-ethoxycoumarin O-deethylase and mutagenicity of 2-amino-3-methylimidazo[4,5-f]quinoline.

The antimutagenicity of 17 natural and synthetic anthraquinones was determined using Salmonella typhimurium TA98 against 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in the presence of Aroclor 1254-induced rat hepatic S9. In general, the relationship between the chemical structures of anthraquinones and their antimutagenicity was found to contain one or more of the following features: (i) C9 carbonyl group, (ii) hydroxyl group at C1 and C4, (iii) C2 ethyl group, and (iv) C3 methyl group. The inhibitory effect of anthraquinones on 7-ethoxycoumarin O-deethylase (ECD) of Aroclor, 1254-induced hepatic microsomes was also examined. In addition, we studied the effect of anthraquinones on the metabolism of IQ by Aroclor 1254-induced microsomes using high-performance liquid chromatography. The antimutagenicity correlated with the inhibition of cytochrome P-450IA2-linked ECD activity in hepatic microsomes, and with the inhibition of N-hydroxy-IQ formation of IQ metabolism by hepatic microsomes. Moreover, we also examined the antimutagenicity of anthraquinones against synthetic N-hydroxy-IQ. Quinizarin and anthraflavic acid were shown to have more effect on the direct mutagenicity of N-hydroxy-IQ than that of the anthraquinones tested. This might explain why both anthraquinones showed higher antimutagenicity; although they inhibited ECD less. These results suggest that there exist at least two mechanisms of action in modifying roles of anthraquinones on the mutagenicity of IQ: (i) mediation through interaction with microsomal activating enzymes to inhibit the major active metabolite of N-hydroxy-IQ formation and (ii) direct interaction with the proximate metabolite of IQ, N-hydroxy-IQ, to block its attack on DNA.