3-amino-1-4-dimethyl-5h-pyrido(4-3-b)indole and 9-hydroxyellipticine

Autoradiograms obtained 1-4 h after i.v. injection of the 14C-labelled carcinogenic tryptophan pyrolysis product Trp-P-1 to albino and pigmented mice showed a pronounced uptake of radioactivity in the lymphatic system (thymus, lymph nodes, bone marrow and spleen), in the endocrine system (hypophysis, thyroid, adrenal medulla) and in the liver, kidney medulla and brain. High radioactivity was present in the excretory pathways, predominantly in the bile/intestinal contents. At longer post-injection times (24 h to 6 days) most of the labelled substance had left the tissues, except for the liver which still retained a high concentration of radioactivity. Trp-P-1 is known to be activated by cytochrome P-448. The uptake of radioactivity in the liver could be reduced by pretreatment with the cytochrome P-448 inhibitor 9-hydroxyellipticine suggesting that the observed accumulation of radioactivity in the liver was partly due to metabolites of Trp-P-1. After pretreatment with the cytochrome P-448 inducer beta-naphthoflavone, the administration of Trp-P-1 resulted in a highly selective accumulation of radioactivity in the lung parenchyma, exceeding all other tissues in the body. beta-Naphthoflavone pretreatment also increased the uptake of radioactivity in the kidney cortex and small intestinal mucosa. As indicated by a high labelling of the pigmented tissues of the maternal and fetal eye, the carcinogen and/or its metabolites were accumulated in melanin.

Topics: Alkaloids; Animals; Benzoflavones; beta-Naphthoflavone; Carbolines; Ellipticines; Endocrine Glands; Female; Fetus; Flavonoids; Indoles; Intestinal Mucosa; Kidney; Kinetics; Liver; Lung; Lymphatic System; Mice; Mice, Inbred C57BL; Mutagens; Pigmentation; Pregnancy; Tissue Distribution