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.
Hao
N J
NJ
Institute of Biochemistry, Chung Shan Medical and Dental College, Taichung, Taiwan, ROC.
Huang
M P
MP
Lee
H
H
D015660:7-Alkoxycoumarin O-Dealkylase / Q000037:antagonists & inhibitors*; D000818:Animals; D000880:Anthraquinones / Q000737:chemistry / Q000494:pharmacology*; D016587:Antimutagenic Agents / Q000737:chemistry*; D001711:Biotransformation / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D007093:Imidazoles / Q000037:antagonists & inhibitors / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D009153:Mutagens / Q000378:metabolism*; D011804:Quinolines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012486:Salmonella typhimurium / Q000187:drug effects; D013329:Structure-Activity Relationship
D000880:Anthraquinones; D016587:Antimutagenic Agents; D007093:Imidazoles; D007527:Isoenzymes; D009153:Mutagens; D011804:Quinolines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; C032012:2-hydroxyamino-3-methylimidazolo(4,5-f)quinoline; C034890:1,4-dihydroxyanthraquinone; D003577:Cytochrome P-450 Enzyme System; D015660:7-Alkoxycoumarin O-Dealkylase; C061208:1-hydroxyanthraquinone