The metabolism of indole alkaloid tumor promoter, (-)-indolactam V, which has the fundamental structure of teleocidins, by rat liver microsomes.
Metabolic activation and/or deactivation of indole alkaloid tumor promoter, (-)-indolactam V (ILV), was examined using rat liver microsomes. Reaction of ILV with the microsomes supplemented with NADPH and MgCl2 gave three major metabolites, which were identified as (-)-N13-desmethylindolactam V and two diastereomers of (-)-2-oxyindolactam V at C-3. The tumor-promoting activities of these metabolites were evaluated by induction of Epstein-Barr virus early antigen and inhibition of specific binding of [3H]-12-O-tetradecanoylphorbol-13-acetate to a mouse epidermal particulate fraction, and proved to be conspicuously lower than that of ILV. These results demonstrate that the metabolism of ILV results in detoxification, and that it itself is the tumor-promoting entity. Studies on the enzymes concerned with this metabolism suggested the involvement of cytochrome P-450-containing mixed-function oxidases. Similar deactivation seems to be possible by skin, where the mixed-function oxidases are known to exist.
D000818:Animals; D000956:Antigens, Viral / Q000096:biosynthesis; D002273:Carcinogens / Q000378:metabolism*; D066298:In Vitro Techniques; D007211:Indoles / Q000378:metabolism*; D007769:Lactams / Q000378:metabolism*; D008235:Lyngbya Toxins / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000032:analysis; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism; D014316:Tritium
D000956:Antigens, Viral; D002273:Carcinogens; C033305:Epstein-Barr virus early antigen; D007211:Indoles; D007769:Lactams; D008235:Lyngbya Toxins; D014316:Tritium; C022176:teleocidins; C043969:indolactam V; D006899:Mixed Function Oxygenases; D013755:Tetradecanoylphorbol Acetate; D010634:Phenobarbital