Possibility of the involvement of 9H-pyrido[3,4-b]indole (norharman) in carcinogenesis via inhibition of cytochrome P450-related activities and intercalation to DNA.
This study investigated the inhibitory effect of 9H-pyrido[3,4-b]indole (norharman), one of the naturally occurring beta-carbolines, on cytochrome P450 (CYP)-related activities and the relationship between its inhibitory effect, its intercalation to DNA, and its comutagenic effect. Norharman reduced the mutagenicities of heterocyclic amines (HCAs) containing 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1), aflatoxin B1, benzo[a]pyrene (BP), and some nitrosamines in the presence of 10 microl liver S9 (20.9 microg protein/ml) from polychlorinated biphenyl-treated rats. Norharman inhibited microsomal CYP-related enzyme activities and CO-binding to the CYP heme (50% inhibitory concentration (IC50), 0.07-6.4 microg/ml). It also inhibited the formation of 3-hydroxyamino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (N-OH-Glu-P-1) and was a noncompetitive-inhibitor of CYP1A-related activities, while it enhanced the direct mutagenicity of N-OH-Glu-P-1 (50% effective concentration, 25.0 microg/ml) and inhibited topo I activity (IC50, 31.0 microg/ml). In the presence of norharman, S9 up to 100 microl incrementally enhanced the mutagenicities of HCAs, BP and dimethylnitrosamine. These data clarified that norharman acts as an inhibitor of the CYP-mediated biotransformation of Glu-P-1 via inhibition of O2-binding to CYP heme, and its inhibition of CYP enzymes occurs at much lower concentration than that for its intercalation to DNA. It is indicated that norharman's inhibitory effect on CYP results in the inhibition of excess metabolism by S9 and this is more likely the mechanism for comutagenic action than the intercalation. Norharman's inhibition of CYP and its enhancement of the N-OH-Glu-P-1 mutagenicity suggest that beta-carbolines modulate chemical carcinogenesis by controlling the xenobiotic metabolism and by intercalating to DNA.
Nii
Hiroaki
H
Laboratory of Radiochemistry, Gifu Pharmaceutical University, 5-6-1 Mitahorahigashi, Gifu 502-8585, Japan. nii@gifu-pu.ac.jp
D000818:Animals; D002243:Carbolines; D002273:Carcinogens / Q000633:toxicity*; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D006247:Harmine / Q000031:analogs & derivatives* / Q000633:toxicity*; D007093:Imidazoles / Q000633:toxicity; D007364:Intercalating Agents / Q000633:toxicity*; D008297:Male; D009251:NADPH-Ferrihemoprotein Reductase / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D059004:Topoisomerase I Inhibitors
D002243:Carbolines; D002273:Carcinogens; D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D007364:Intercalating Agents; D059004:Topoisomerase I Inhibitors; D006247:Harmine; C023785:2-amino-6-methyldipyrido(1,2-a-3',2'-d)imidazole; C023786:2-hydroxyamino-6-methyldipyrido(1,2-a-3',2'-d)imidazole; C010262:norharman; D009251:NADPH-Ferrihemoprotein Reductase