568. The Fischer indolisation of cyclohexane-1,4-dione bisphenylhydrazone

Robinson, B.

doi:10.1039/jr9630003097

Cited by 52 publications

(38 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1 analog d) and ICZ ( Fig. 1 analog c) according to published methods (18,19). We isolated 2-(indol-3-ylmethyl)-3,3'-diindolylmethane (LT) ( (Fig.…”

Section: Methodsmentioning

confidence: 99%

Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Bjeldanes

Kim

Grose

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

515

379

View full text Add to dashboard Cite

Indole-3-carbinol (13C) is a secondary plant metabolite produced in vegetables of the Brassica genus, including cabbage, cauliflower, and brussels sprouts. I3C is both an anti-initiator and a promoter of carcinogenesis. Consumption of 13C by humans and rodents can lead to marked increases in activities ofcytochrome P-450-dependent monooxygenases and in a variety ofphase II drug-metabolizing enzymes. We have reported previously that the enzyme-inducing activity of 13C is mediated through a mechanism requiring exposure of the compound to the low-pH environment of the stomach. We report here the aromatic hydrocarbon responsiveness-receptor Kd values (22 nM-90 nM), determined with C57BL/6J mouse liver cytosol and the in vitro-and in vivo-molar yields (0.1-6%) of the major acid condensation products of 13C. We also show that indolo[3,2-b]carbazole (ICZ) is produced from 13C in yields on the order of 0.01% in vitro and, after oral intubation, in vivo. ICZ has a Kd of 190 pM for aromatic hydrocarbon responsiveness-receptor binding and an EC50 of 269 nM for induction of cytochrome P4501A1, as measured by ethoxyresorufm O-deethylase activity in murine hepatoma Hepa lclc7 cells. The binding affinity of ICZ is only a factor of 3.7 X 10-2 lower than that of the highly toxic environmental contaminant and cancer promoter 2,3,7,8-tetrachlorodibenzo-p-dioxin. ICZ and related condensation products appear responsible for the enzyme-inducing effects of dietary 13C.

show abstract

“…1 analog d) and ICZ ( Fig. 1 analog c) according to published methods (18,19). We isolated 2-(indol-3-ylmethyl)-3,3'-diindolylmethane (LT) ( (Fig.…”

Section: Methodsmentioning

confidence: 99%

Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Bjeldanes

Kim

Grose

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

515

379

View full text Add to dashboard Cite

show abstract

“…Cultures were diluted 1:6 in fresh medium and grown overnight in the absence or presence of either omeprazole or the high affinity dioxin receptor ligand indolo [3,2-b]carbazole, synthesized as described (48). Omeprazole analogues, timoprazole (TI), and desoxytimoprazole (D-TI), were prepared as described (49).…”

Section: Methodsmentioning

confidence: 99%

Regulation of Dioxin Receptor Function by Omeprazole

Dzeletovic

McGuire

Daujat

et al. 1997

Journal of Biological Chemistry

View full text Add to dashboard Cite

The intracellular dioxin (aryl hydrocarbon) receptor mediates signal transduction by dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) and related environmental pollutants and functions as a ligand-activated transcription factor. In this study we have examined the effects on dioxin receptor function of a potentially novel ligand, omeprazole, which is widely clinically used as a gastric anti-ulcer drug. In primary human hepatocytes omeprazole potently induced cytochrome P4501A1 mRNA expression, whereas this effect was not detected in mouse primary hepatocytes. In human hepatoma cells omeprazole was found to induce transcription of reporter genes via the xenobiotic response element that is recognized by the ligand-activated dioxin receptor. In contrast, the human dioxin receptor was not activated by omeprazole upon expression in a receptor-deficient mouse hepatoma cell line. In a reconstituted yeast (Saccharomyces cerevisiae) model system, however, both the mouse and human dioxin receptors were potently activated by omeprazole. Although omeprazole failed to displace dioxin in in vitro ligand binding assays, a residue within the ligand binding domain that is critical for dioxin binding in vitro was also critical for omeprazole responsiveness in vivo. Consistent with this observation, both omeprazole and dioxin responsiveness of the dioxin receptor was inhibited in mutant yeast cells expressing low levels of the molecular chaperone hsp90 that is critical for ligand binding activity. The sulfoxide group that is essential for formation of a planar conversion product of omeprazole was found to be critical for dioxin receptor activation. Taken together, these data suggest that omeprazole represents a precursor for a novel class of dioxin receptor agonists that are bona fide dioxin receptor ligands but generated in a strictly species-specific manner.

show abstract

“…ICZ was prepared by K. Grose (University of California, Berkeley, CA) according to the procedure of Robinson (15). TCDD samples were obtained from B. Ames (University of California, Berkeley, CA) and S. * This work was supported in part by Grant CA49250 from the National Institutes of Health (to L. F.…”

Section: Methodsmentioning

confidence: 99%

“…RNA samples (10,15, or 20 g/lane) were electrophoresed through formaldehydeagarose gels, transferred to a nylon membrane, and probed as described elsewhere (26). The Cyp1a-1 cDNA in PBR322 plasmid (18) which was used as a probe to detect the CYP1A1 mRNA band at 2.9 kilobases, was kindly provided by D. Nebert (University of Cincinnati, OH).…”

Section: Rna Isolation and Analysismentioning

confidence: 99%

Regulation of CYP1A1 by Indolo[3,2-b]carbazole in Murine Hepatoma Cells

Chen¹,

Riby²,

Srivastava³

et al. 1995

Journal of Biological Chemistry

View full text Add to dashboard Cite

To determine the basis for unexpected differences in CYP1A1 inducing potencies and efficacies for the dietderived indole derivative, indolo[3,2-b]carbazole (ICZ) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), we conducted a systematic analysis of events involved in the induced expression of CYP1A1 in murine hepatoma-derived cell lines (Hepa-1). In contrast to the effects of TCDD, induction kinetics and CYP1A1 mRNA half-life were dependent on ICZ concentration, and the response from low doses of inducer was transient due to rapid clearance of ICZ. TCDD and ICZ produced the same maximum response (i.e. equal efficacies) from a TCDDresponsive CAT reporter construct in Hepa-1 cells. When measured by the immediate responses associated with CYP1A1 expression, including cellular uptake of inducer, receptor transformation and binding to DRE (gel mobility shift assay), initiation of transcription (nuclear run-on assay), and short-term accumulation of mRNA (Northern blot assay), ICZ also exhibited an efficacy equal to that of TCDD and a potency that corresponds to its receptor affinity. ICZ is a potent and selective noncompetitive inhibitor of ethoxyresorufin O-deethylase activity (K i ‫؍‬ 1.5 nM). Taken together these results indicate that ICZ is a bifunctional modulator of CYP1A1 expression with intrinsic efficacy equal to that of TCDD. Indolo[3,2-b]carbazole (ICZ)1 (Structure 1) is a compound of dietary origin present in the gastrointestinal tract of rodents and humans. ICZ is produced in vivo and in vitro as one of the acid-catalyzed reaction products of non-nutritive indoles such as indole-3-carbinol and glucobrassicin that are present in cabbage and Brussels sprouts and other plants of the Brassica genus (1-4). ICZ is also produced, presumably from the nutritive indole, tryptophan, as a metabolic product of intestinal bacteria (5).ICZ is similar in several respects to the potent environmental pollutant, TCDD. Both compounds have immunosuppressive activity in murine fetal thymus organ culture and both substances exhibit potent antiestrogenic activities including inhibition of estrogen-dependent growth of cultured breast tumor cells (6, 7). Additionally, both ICZ and TCDD induce CYP1A1 activity in animals and in cultured cells (1). CYP1A1 is a phase I enzyme involved in the metabolism of many drugs and carcinogens. CYP1A1 is also the enzyme thought to be primarily responsible for the inactivation of estradiol in breast tumor cells (8).Perhaps key to these similarities in activities is the fact that ICZ and TCDD are nearly isosteric and both compounds are potent Ah receptor agonists (9, 10). The Ah receptor is a widely occurring, ligand-activated transcription factor that mediates the activation of CYP1A1, CYP1A2, glutathione S-transferase Ya, and quinone reductase genes. Binding to this receptor is thought also to be responsible for most of the toxic effects of TCDD, including tumor promotion, teratogenesis, and lethal anorexia with wasting, that appear to result mechanistically from effects beyond simple induction of...

show abstract

568. The Fischer indolisation of cyclohexane-1,4-dione bisphenylhydrazone

Cited by 52 publications

References 0 publications

Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Regulation of Dioxin Receptor Function by Omeprazole

Regulation of CYP1A1 by Indolo[3,2-b]carbazole in Murine Hepatoma Cells

Contact Info

Product

Resources

About