Protection against Trp-P-2 mutagenicity by purpurin: mechanism of in vitro antimutagenesis

Abstract

chemopreventive agents. There are various protective mechanisms for these agents. Many act by modulating the metabolism Hikoya Hayatsu of procarcinogens to decrease formation of the ultimate carcinoFaculty of Pharmaceutical Sciences, Okayama University, Tsushima naka gens. In contrast, chlorophyllin acts as a chemopreventive agent 1-1-1, Okayama 700 8530, Japan by complex formation with aromatic carcinogens, possibly Purpurin (1,2,4-trihydroxy-9,10-anthraquinone) is a natpreventing their absorption from the gut (Arimoto et al., 1993). ural pigment isolated from madder root (Rubia tinctorum) Purpurin (1,2,4-trihydroxy-9,10-anthraquinone) ( Figure 1A) which inhibits the mutagenicity of a number of heterocyclic is a pigment isolated from madder root (Rubia tinctorum). It amines in the Ames mutagenicity test. Two effects were is non-mutagenic in the majority of Ames tester strains in the observed in the presence of purpurin. The rate of degradapresence and absence of S9 (Westendorf et al., 1990; Kawasaki tion of 3-hydroxyamino-1-methyl-5H-pyrido[4,3-b]indole et al., 1992) and only weakly mutagenic in TA1537 (Westendorf [Trp-P-2(NHOH)] at neutral pH was increased. The major et al., 1990). We have previously investigated the effect of product of this purpurin-dependent degradation was identithis pigment on heterocyclic amine-induced mutagenicity in fied as the parent amine 3-amino-1-methyl-5H-pyrido[4,3-the Ames test (Marczylo et al., 1999) and found it to be an b]indole (Trp-P-2). Secondly, the rate of Trp-P-2 efficient inhibitor of 3-hydroxyamino-1-methyl-5H-pyrido[4,3-N-hydroxylation, the major route of bioactivation, by PCBb]indole [Trp-P-2(NHOH)]-induced mutations comparable treated rat hepatic microsomes was markedly decreased.with the recognized chemopreventive agents chlorophyllin and Cytochrome P450-dependent O-dealkylation of methoxy-, (-)epigallocatechin gallate (Marczylo et al., 1999). In both the ethoxy-and pentoxyresorufin by these microsomes was also presence and absence of rat hepatic S9, incubation is required significantly inhibited by purpurin. The nature of this for purpurin to be antimutagenic (Marczylo et al., 1999). A inhibition was competitive. Spectrophotometric investidecrease in Trp-P-2(NHOH) mutagenicity in the absence of gations suggest no direct interaction between Trp-P-2 and S9 implies that this decrease is a result of some direct purpurin. Furthermore, no evidence for Trp-P-2 binding interaction between the mutagen and purpurin. The mutagenic was observed with carminic acid, a structural analog response to 3-amino-1-methyl-5H-pyrido [4,3-b]indole (Trp-Pof purpurin, when it was immobilized on ω-aminohexyl 2) of Salmonella typhimurium TA1538ARO, a strain expressing agarose. Therefore, in vitro the proposed mechanism by recombinant human CYP1A2, CYP reductase and bacterial Owhich purpurin protects against heterocyclic amineacetyltransferase, was also markedly decreased after preincubainduced mutagenesis involves competitive inhibition of tion of the bacterial culture with purpurin (Marcz...

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