Metabolic activation of Trp-P-2, a tryptophan-pyrolysis mutagen, by isolated rat hepatocytes.
Metabolic activation of a tryptophan-pyrolysis product, 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), by isolated rat hepatocytes was studied. The substrate (Trp-P-2) disappearance by hepatocytes from untreated rats was slow, but enhanced by 3-methylcholanthrene (MC) pretreatment of rats. The covalent binding of Trp-P-2 to cellular macromolecules was detected in hepatocytes from untreated rats. The amount of covalent binding of Trp-P-2 to protein and RNA was greater than that to DNA. The covalent binding to Trp-P-2 to DNA, RNA and protein in hepatocytes from untreated rats was about 5-10 times less than that in hepatocytes from MC-pretreated rats. 7,8-Benzoflavone strongly inhibited the substrate disappearance and the binding of Trp-P-2 to DNA in hepatocytes from MC-pretreated rats. These results indicate that Trp-P-2 is metabolically activated by the P-448 type of cytochrome P-450 which is induced by MC. Diethylmaleate enhanced by about 50% the binding of Trp-P-2 to DNA in hepatocytes from MC-pretreated rats. On the other hand, cysteine inhibited the binding of Trp-P-2 to DNA with a concomitant reduction in the accumulation of the active metabolite, N-hydroxy-Trp-P-2 (N-OH-Trp-P-2). Sulfhydryl compounds seemed to play important roles in the detoxification of Trp-P-2.
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D001711:Biotransformation / Q000187:drug effects; D002243:Carbolines / Q000378:metabolism*; D003545:Cysteine / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D007211:Indoles / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008298:Maleates / Q000494:pharmacology; D008748:Methylcholanthrene / Q000494:pharmacology; D009153:Mutagens / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D001571:Benzoflavones; D002243:Carbolines; D007211:Indoles; D008298:Maleates; D009153:Mutagens; D011506:Proteins; D008748:Methylcholanthrene; C011512:alpha-naphthoflavone; D012313:RNA; C019133:3-amino-1-methyl-5H-pyrido(4,3-b)indole; D004247:DNA; C014476:diethyl maleate; D003545:Cysteine