Protection against Trp-P-2 mutagenicity by purpurin: mechanism of in vitro antimutagenesis.
Purpurin (1,2,4-trihydroxy-9,10-anthraquinone) is a natural pigment isolated from madder root (Rubia tinctorum) which inhibits the mutagenicity of a number of heterocyclic amines in the Ames mutagenicity test. Two effects were observed in the presence of purpurin. The rate of degradation of 3-hydroxyamino-1-methyl-5H-pyrido¿4,3-bĭndole ¿Trp-P-2(NHOH) at neutral pH was increased. The major product of this purpurin-dependent degradation was identified as the parent amine 3-amino-1-methyl-5H-pyrido¿4,3-bĭndole (Trp-P-2). Secondly, the rate of Trp-P-2 N-hydroxylation, the major route of bioactivation, by PCB-treated rat hepatic microsomes was markedly decreased. Cytochrome P450-dependent O-dealkylation of methoxy-, ethoxy- and pentoxyresorufin by these microsomes was also significantly inhibited by purpurin. The nature of this inhibition was competitive. Spectrophotometric investigations suggest no direct interaction between Trp-P-2 and purpurin. Furthermore, no evidence for Trp-P-2 binding was observed with carminic acid, a structural analog of purpurin, when it was immobilized on omega-aminohexyl agarose. Therefore, in vitro the proposed mechanism by which purpurin protects against heterocyclic amine-induced mutagenesis involves competitive inhibition of cytochrome P450-dependent bioactivation and accelerated degradation of the N-hydroxylamine to the parent amine.
Marczylo
T
T
Faculty of Pharmaceutical Sciences, Okayama University, Tsushima naka 1-1-1, Okayama 700 8530, Japan. tom@aber.ac.uk
Arimoto-Kobayashi
S
S
Hayatsu
H
H
D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D016587:Antimutagenic Agents / Q000494:pharmacology*; D001673:Biodegradation, Environmental; D001711:Biotransformation; D002243:Carbolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D002329:Carmine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D004396:Coloring Agents / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology*; D018517:Plant Roots; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects*
D000880:Anthraquinones; D016587:Antimutagenic Agents; D002243:Carbolines; D004396:Coloring Agents; D009153:Mutagens; C019133:3-amino-1-methyl-5H-pyrido(4,3-b)indole; D002329:Carmine; C511975:purpurin anthraquinone