Certain tryptophan photoproducts are inhibitors of cytochrome P450-dependent mutagenicity.
Two photoproducts, derived from UV-irradiation of the amino acid L-tryptophan and with high Ah (TCDD) receptor binding affinity, were tested for genotoxic and antimutagenic effects. The two indolo[3,2-b]carbazole derivatives, with the molecular weights of 284 and 312, respectively, were tested in Saccharomyces cerevisiae strain D7 for mitotic gene conversion and reverse mutation and in strain RS112 for sister chromatid conversion and gene conversion. No significant (P > 0.05) genotoxic effects were found in strain D7, while strain RS112 showed a small but significant increase in the frequency of sister chromatid conversions. In Chinese hamster ovary (CHO) cells the two compounds induced a statistically significant but less than twofold increase in the frequency of sister chromatid exchanges (SCE). No mutations were detected when the compounds were tested in Salmonella typhimurium strains TA98 and TA100. However, both 284 and 312 acted as antimutagens on strain TA100 + S9 in the presence of benzo(a)pyrene. The decrease in mutagenicity by the most potent compound 284 was 20 revertants/nmol. This effect could be explained by an inhibitory effect on the cytochrome P450-dependent ethoxyresorufin O-deethylase (EROD) activity as seen in rat hepatocytes. The two compounds were also tested with hamster cells expressing rat cytochrome P-450IA1. The results support the conclusion that this cytochrome P-450 isozyme is inhibited by the tryptophan photoproducts. Similar results were also seen with two other high affinity Ah receptor ligands the quinazolinocarboline alkaloids rutaecarpine and dehydrorutaecarpine.
Rannug
U
U
Department of Genetics, Stockholm University, Sweden.
Agurell
E
E
Rannug
A
A
Cederberg
H
H
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D016587:Antimutagenic Agents; D016466:CHO Cells / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology* / Q000633:toxicity; D006224:Cricetinae; D003412:Cricetulus; D019363:Cytochrome P-450 CYP1A1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005785:Gene Conversion; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D026121:Indole Alkaloids; D007211:Indoles / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D016296:Mutagenesis / Q000187:drug effects*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity; D009154:Mutation; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000378:metabolism; D012044:Regression Analysis; D012441:Saccharomyces cerevisiae / Q000235:genetics; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D012854:Sister Chromatid Exchange; D013489:Suppression, Genetic; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000528:radiation effects; D014466:Ultraviolet Rays; D052999:Quinazolinones
D000470:Alkaloids; D016587:Antimutagenic Agents; D002227:Carbazoles; D019363:Cytochrome P-450 CYP1A1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D007041:Hypoxanthine Phosphoribosyltransferase; D026121:Indole Alkaloids; D007211:Indoles; D009153:Mutagens; D010088:Oxidoreductases; D011799:Quinazolines; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D014364:Tryptophan; C075954:indolo(3,2-b)carbazole; C028632:rutecarpine; D052999:Quinazolinones