Tryptanthrins: a novel class of agonists of the aryl hydrocarbon receptor.
2,3,7,8-Tetrachlorodibenzo-p-dioxin and related environmental pollutants exert most of their adverse effects such as immunosuppression, induction of endocrine dysfunction, tumor promotion, and teratogenicity via the aryl hydrocarbon or dioxin receptor. While most potent agonists of the aryl hydrocarbon receptor are of synthetic origin, an increasing number of natural compounds are now recognized as receptor agonists. Our findings demonstrated that some tryptanthrin derivatives biosynthesized in incubations of Candida lipolytica with tryptophan and anthranilic acid or its derivatives were agonists of the aryl hydrocarbon receptor. The biosynthetic products 8-methyltryptanthrin, 8-chlorotryptanthrin, and 8-bromotryptanthrin induced cytochrome P4501A1 mRNA and protein in rat hepatocytes in primary culture, characteristic features of aryl hydrocarbon receptor agonists. Log-probit analysis of the catalytic activity of cytochrome P4501A1, 7-ethoxyresorufin O-deethylase (EROD), revealed EC50 induction values of 1.7, 0.25, and 0.17 microM for 8-methyltryptanthrin, 8-chlorotryptanthrin, and 8-bromotryptanthrin, respectively. Interestingly, the nonsubstituted tryptanthrin molecule, biosynthesized from the common physiological precursors tryptophan and anthranilic acid, was also active as an inducer. The specificity of the inducing effect of tryptanthrins was demonstrated in gel retardation experiments in Hepa-1 mouse hepatoma cells, showing the characteristic interaction of the activated aryl hydrocarbon receptor with an oligonucleotide containing a xenobiotic-responsive element. It is suggested that the receptor may be part of a defense system protecting higher organisms from secondary metabolites formed by the microflora of the host or its environment.
Schrenk
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D
Institute of Toxicology, University of Tübingen, Germany. dieter.schrenk@uni-tuebingen.de
Riebniger
D
D
Till
M
M
Vetter
S
S
Fiedler
H P
HP
D000818:Animals; D002175:Candida / Q000378:metabolism*; D002478:Cells, Cultured; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D000072317:Polychlorinated Dibenzodioxins; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012313:RNA / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000072317:Polychlorinated Dibenzodioxins; D011799:Quinazolines; D018336:Receptors, Aryl Hydrocarbon; C046243:tryptanthrine; D012313:RNA; D007770:L-Lactate Dehydrogenase; D002786:Cholesterol Side-Chain Cleavage Enzyme