Discovery and biological characterization of 1-(1H-indol-3-yl)-9H-pyrido[3,4-b]indole as an aryl hydrocarbon receptor activator generated by photoactivation of tryptophan by sunlight

doi:10.1016/j.cbi.2011.05.010

Chemico-Biological Interactions

Volume 193, Issue 2, 5 September 2011, Pages 119-128

https://doi.org/10.1016/j.cbi.2011.05.010 Get rights and content

Abstract

Activation of the aryl hydrocarbon receptor (AHR) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is required for AHR dependent transcriptional activation and TCDD toxicity. We previously reported that aqueous tryptophan exposed to sunlight through window glass (aTRP) contains multiple photoproducts, including the well characterized 6-formylindolo[3,2-b]carbazole (FICZ), capable of activating the AHR and inducing CYP1A and CYP1A-mediated enzyme activities. We report here the isolation from aTRP and chemical characterization and synthesis of 1-(1H-indol-3-yl)-9H-pyrido[3,4-b]indole (IPI), a compound previously identified as a natural product of marine ascidia and now shown to be a TRP photoproduct with AHR-inducing properties. IPI, FICZ and TCDD produced equieffective induction of CYP1A-mediated 7-ethoxyresorufin deethylase (EROD) activity in chick embryo primary hepatocytes and mammalian Hepa1c1c7 cells. EROD induction by IPI was markedly curtailed in AHR-defective c35 cells, supporting the AHR dependence of the IPI response. Although IPI had a higher EC₅₀ for EROD induction than FICZ, the much larger amount of IPI than FICZ in aTRP makes IPI a prominent contributor to EROD induction in aTRP. IPI was detected in TRP-containing culture medium under ambient laboratory conditions but not in TRP-free medium, consistent with its production from TRP. Cotreatment of hepatocytes with submaximal EROD-inducing doses of IPI and FICZ or TCDD produced additive increases in EROD without synergistic or inhibitory interactions. IPI and FICZ were readily metabolized by cultured hepatocytes. In addition to increasing CYP1A4 mRNA and EROD, IPI and FICZ decreased hepatocyte phosphoenolpyruvate carboxykinase mRNA expression and glucose output, biological effects associated with TCDD metabolic dysregulation. The findings underscore a role for sunlight in generating AHR-activating bioactive molecules.

Highlights

► Sunlight has an important role in generating bioactive molecules that can activate the AHR. ► Identification of 1-(1H-indol-3-yl)-9H-pyrido[3,4-b]indole (IPI) as a new AHR-inducing tryptophan (TRP) photoproduct. ► IPI induces AHR-mediated P450 activity (EROD) and suppresses glucose output. ► IPI, a prominent component of photoactivated TRP, induces EROD additively with FICZ or TCDD. ► IPI was detected in tissue culture medium in ordinary ambient light conditions.

Introduction

The environmental toxin and industrial by-product TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin, dioxin) is the most potent and best studied activator of the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor and member of the Per-Arnt-Sim (PAS) protein family [1], [2]. Activation of the AHR by TCDD elicits diverse pathological effects, including tumor promotion and metabolic dysregulation leading to a wasting syndrome [1], [2], [3].

Ligand activation causes the AHR to migrate from cytosol to the nucleus and form a complex with the aryl hydrocarbon nuclear translocator (ARNT) that can bind dioxin-responsive elements (DREs) in the promoter regions of target genes including xenobiotic-metabolizing cytochrome P450 (CYP1A) enzymes and TCDD-inducible poly [ADP-ribose] polymerase (TiPARP, PARP7) [4]. In addition to environmental toxins like TCDD, some natural products have recently been shown to activate the AHR, among which tryptophan (TRP) derivatives comprise a large group [5]. These include TRP derivatives ingested in the diet or produced by metabolism in vivo, such as indolo[3,2-b]carbazole (ICZ) [6], and photoproducts formed by exposure of TRP to UV or visible light [7], [8], [9], among which 6-formylindolo[3,2-b]carbazole (FICZ) is the best characterized [10]. The discovery of natural compounds that can bind and activate the AHR has stimulated a search for diverse AHR ligands that may elicit pathologic effects (e.g., tumorigenesis, metabolic dysregulation) or as yet unrecognized physiologic activities of the AHR.

We previously reported that exposure of an aqueous solution of TRP to sunlight passing through window glass (aTRP) produces multiple photoproducts capable of activating the AHR and inducing CYP1A-mediated enzyme activities, including arachidonic acid epoxygenation and 7-ethoxyresorufin deethylation (EROD) [8]. FICZ was identified in one of 14 fractions obtained by separation of aTRP by reverse phase high pressure liquid chromatograph (RP-HPLC), all of which exhibited CYP1A inducing capacity. That prior study showed that photoactivated TRP contains many AHR inducers in addition to FICZ. We report here the identification, chemical characterization and synthesis of a novel photoproduct present in aTRP that induces CYP1A with high efficacy: 1-(1H-indol-3-yl)-9H-pyrido[3,4-b]indole (IPI).

Section snippets

Materials

Chemicals were from Sigma–Aldrich, (St. Louis, MO), TCI (Portland, OR) or Alfa Aesar (Ward Hill, MA) and were used without further purification. Tissue culture medium and additives were from GIBCO BRL Life Technologies (Gaithersburg, MD). HPLC chemicals were of HPLC or LC/MS grade. Fertilized White Leghorn chicken eggs were obtained from Burr Farm (Hampton, CT), TCDD was from the NCI Chemical Carcinogen Repository, (Kansas City, MO) and FICZ was from Biomol/Enzo Life Sciences (Plymouth Meeting,

Isolation of the main EROD inducing peaks in fraction 7 of 14 fractions collected from RP-HPLC separation of an aTRP solution exposed to sunlight for 7 days

We previously reported [8] the separation by HPLC of 14 UV-absorbing fractions in a solution of activated tryptophan (aTRP) after a 7-day exposure to sunlight and found that all of the fractions induced EROD activity to varying extents (Fig. 1A). Since fraction 7 (F7) produced substantial EROD induction with fewer UV absorbing peaks than prior eluting fractions, it seemed likely to contain a prominent and effective EROD inducer. Therefore, we set out to identify the main EROD-inducing molecular

Discussion

We report here the discovery of a novel TRP photoproduct with AHR-inducing properties generated by exposure of an aqueous solution of TRP to sunlight passing through window glass. The compound was purified from a mixture of photoproducts, the chemical formula was assigned by accurate mass measurement and a putative structure 1-(1H-indol-3-yl)-9H-pyrido[3,4-b]indole (to which we have assigned the acronym “IPI”), was proposed on the basis of extensive MS/MS and pseudo MS³ analyses. IPI was

Conflict of interest statement

None declared.

Acknowledgments

This work was supported by NIH Grants ES03606 (ABR), HL87062 (SSG) and RR27305 (SSG), and by a grant from the Winston Foundation (ABR). TCDD was provided by the National Cancer Institute’s Chemical Carcinogen Reference Standards Repository operated under contract by Midwest Research Institute, Kansas City, MO, NO2-CB-666000. We thank Dr. Ivan Haller for his helpful input and discussions during the initial phase of this work.

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Regulation of the Immune Response by the Aryl Hydrocarbon Receptor
2018, Immunity
Citation Excerpt :
Finally, exposure of Trp to ultraviolet light triggers its photo-oxidation to 6-formylindolo[3,2-b]carbazole (FICZ), a potent AhR ligand (Rannug et al., 1987; Wincent et al., 2009), with broad implications in UV light response, genomic stability, circadian rhythms, and the immune response (Quintana et al., 2008; Veldhoen et al., 2008; Wincent et al., 2012). Additional Trp photometabolites exist, such as 1-(1H-indol-3-yl)-9H-pyrido[3,4-b]indole, which exhibits a potency similar to that of FICZ (Diani-Moore et al., 2011). These photometabolites may have both local effects in the skin and also systemic effects because FICZ has been detected in human urine (Wincent et al., 2012).
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is activated by small molecules provided by the diet, microorganisms, metabolism, and pollutants. AhR is expressed by a number of immune cells, and thus AhR signaling provides a molecular pathway that integrates the effects of the environment and metabolism on the immune response. Studies have shown that AhR signaling plays important roles in the immune system in health and disease. As its activity is regulated by small molecules, AhR also constitutes a potential target for therapeutic immunomodulation. In this review we discuss the role of AhR in the regulation of the immune response in the context of autoimmunity, infection, and cancer, as well as the potential opportunities and challenges of developing AhR-targeted therapeutics.
Time-dependent transcriptomic and biochemical responses of 6-formylindolo[3,2-b]carbazole (FICZ) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are explained by AHR activation time
2016, Biochemical Pharmacology
Citation Excerpt :
Interestingly, the LC50 (95% CI) value estimated for FICZ in CEH [14,000 nM (12,000–16,000 nM)] was approximately similar to the LC50 (95% CI) value in COS-7 cells [9400 nM (4700–19,000 nM)] [11]. FICZ was shown to be readily metabolized by cultured hepatocytes [56,8], while the results of our previous study demonstrated that COS-7 cells express no or very low levels of CYP1A to metabolize FICZ [11]. Thus, an approximately equal sensitivity of CEH and COS-7 cells to FICZ suggests that the ability of CEH to rapidly metabolize FICZ does not significantly increase their tolerance to FICZ toxicity.
6-Formylindolo[3,2-b]carbazole (FICZ) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are ligands of the aryl hydrocarbon receptor (AHR) and bind to the AHR with high affinity. Until recently, TCDD was considered to be the most potent AHR agonist, but several recent studies indicate that FICZ binds with greater affinity to the AHR than TCDD. To advance our understanding of the similarities and differences of the effects of FICZ and TCDD exposure in chicken embryo hepatocyte (CEH) cultures, we compared relative expression changes of 27 dioxin-responsive genes by the use of a chicken PCR array, porphyrin accumulation and ethoxyresorufin-O-deethylase (EROD) activity at different time points. In addition, an egg injection study was performed to assess the effects of FICZ on the developing chicken embryo. The results of the current study showed: (1) mean EROD-derived relative potency values for FICZ compared to TCDD changed as a function of time (i.e. 9, 0.004, 0.0008 and 0.00008 at 3, 8, 24, and 48 h, respectively) in CEH cultures; (2) FICZ exposure did not result in porphyrin accumulation in CEH cultures; (3) concordance between gene expression profiles for FICZ and TCDD was time- and concentration-dependent, and (4) no mortality or morphological abnormalities were observed in chicken embryos injected with 0.87 ng FICZ/g egg into the air cell. The results presented herein suggest that while FICZ and TCDD share similar molecular targets, transient versus sustained AHR activation by FICZ and TCDD result in differential transcriptomic responses. Moreover, rapid metabolism of FICZ in hepatocytes resulted in a significant decrease in the induction of EROD activity.
Sensitivity of avian species to the aryl hydrocarbon receptor ligand 6-formylindolo [3,2-b] carbazole (FICZ)
2014, Chemico-Biological Interactions
Citation Excerpt :
Approximately equal EC50 and ReP values for FICZ were observed at different time-points in COS-7 cells transfected with chicken AHR1 construct (Table 3). However, previous studies showed that the EC50 and ReP values for FICZ were changed dramatically over time in other cell types because FICZ was extensively metabolized [7,20,23,41]. Our findings suggest that such metabolism of FICZ in COS-7 cells does not occur.
Avian species differ in sensitivity to the toxic effects of dioxin-like compounds (DLCs) and recent reports have provided insight into the molecular mechanisms underlying this variability. The sensitivity of avian species to DLCs is associated with the identity of amino acids at positions 324 and 380 within the ligand-binding domain (LBD) of the aryl hydrocarbon receptor 1 (AHR1). 6-formylindolo [3,2-b] carbazole (FICZ), a naturally produced photo-oxidation product of tryptophan, is a highly potent AHR ligand. Few studies have attempted to determine if there are species differences in AHR activation by FICZ in a systematic manner. Here we describe results from an in vitro assay that measures AHR1-mediated luciferase reporter gene activity to determine concentration-dependent effects of FICZ and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in COS-7 cells transfected with AHR1 constructs from chicken (Gallus gallus domesticus), ring-necked pheasant (Phasianus colchicus), Japanese quail (Coturnix japonica) and common tern (Sterna hirundo), and three mutant AHR1 constructs. Data were used to (a) compare the potency of FICZ and TCDD for each AHR1 construct (relative potency; ReP) and (b) the sensitivity of each construct to AHR1 activation by FICZ and TCDD (relative sensitivity; ReS). The results show that (1) FICZ was considerably more potent than TCDD in cells transfected with chicken AHR1 (ReP_avg = 41), ring-necked pheasant AHR1 (ReP_avg = 93), Japanese quail AHR1 (ReP_avg = 1392) and common tern AHR1 (ReP_avg = 1534), (2) there were no significant differences in sensitivity to FICZ in cells expressing chicken, pheasant, quail and tern AHR1, but there were significant differences in sensitivity to TCDD, (3) alteration of amino acids at positions 324 and 380 had no effect on avian AHR1 activity in response to FICZ, (4) there was no time-dependent change in the relative potency of FICZ in COS-7 cells, and (5) neither FICZ nor TCDD induced ethoxyresorufin O-deethylase (EROD activity) in COS-7 cells. Our results suggest that FICZ and TCDD activate avian AHR1 by different modes of interaction with AHR1.
Aryl hydrocarbon receptor activation by dioxin targets phosphoenolpyruvate carboxykinase (PEPCK) for ADP-ribosylation via 2,3,7,8-Tetrachlorodibenzo-p- dioxin (TCDD)-inducible poly(ADP-ribose) polymerase (TiPARP)
2013, Journal of Biological Chemistry
Citation Excerpt :
Second, it seems likely that AHR effects on ADP-ribosylation shown here will have implications beyond TCDD toxicity. There is increasing interest in biologic effects of natural AHR ligands present in food, in the environment, or generated in the body (59–62) and in AHR effects on physiologic processes, most conspicuously, immune and gastrointestinal system function (63–65). In fact, a role for TiPARP in TCDD modification of immune system function has been suggested (66).
Effects of the environmental toxin and carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) include a wasting syndrome associated with decreased gluconeogenesis. TCDD is a potent activator of the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor. The relationship between gene activation by the AHR and TCDD toxicities is not well understood. We recently identified a pathway by which the AHR target gene TiPARP (TCDD-inducible poly(ADP-ribose) polymerase) contributes to TCDD suppression of transcription of phosphoenolpyruvate carboxykinase (PEPCK), a key regulator of gluconeogenesis, by consuming NAD⁺ and decreasing Sirtuin 1 activation of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), a transcriptional activator of PEPCK. We report here that TCDD-induced TiPARP also targets PEPCK for ADP-ribosylation. Both cytosolic and mitochondrial forms of PEPCK were found to undergo ADP-ribosylation. Unexpectedly, AHR suppression also enhanced ADP-ribosylation and did so by a poly(ADP-ribose) polymerase-independent mechanism. This report 1) identifies ADP-ribosylation as a new posttranslational modification for PEPCK, 2) describes a pathway by which transcriptional induction of TiPARP by the AHR can lead to a downstream posttranslational change in a TCDD target protein (PEPCK), and 3) reveals that the AHR exerts complex, previously unidentified modulatory effects on ADP-ribosylation.
Background: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-activated aryl hydrocarbon receptor (AHR) decreases gluconeogenesis by suppressing phosphoenolpyruvate carboxykinase (PEPCK) transcription via TCDD-inducible poly(ADP-ribose)-polymerase (TiPARP).
Results: AHR enhances PEPCK ADP-ribosylation through TiPARP, and AHR suppression increases ADP-ribosylation PARP-independently.
Conclusion: ADP-ribosylation, a new PEPCK posttranslational modification, is subject to complex regulation by the AHR.
Significance: AHR gene activation leads to ADP-ribosylation of PEPCK with implications for energy metabolism beyond TCDD toxicity.
Simultaneous alterations of brain and plasma serotonin concentrations and liver cytochrome P450 in rats fed on a tryptophan-free diet
2012, Pharmacological Research
Citation Excerpt :
On the other hand, the decreased plasma tryptophan level may additionally affect cytochrome P450 expression in a more direct way (not only via the nervous system). It has been shown that tryptophan or its indole derivatives increase hepatic protein synthesis, cytochrome P450 content, and the enzyme activity of rats and other species in vitro and in vivo [46–51]. Moreover, tryptophan is an amino acid which is essential for the synthesis of cytochrome P450.
Our previous study suggested involvement of the brain serotonergic system in the regulation of liver cytochrome P450 (CYP). The aim of the present study was to demonstrate simultaneous responsiveness of liver CYP and the peripheral and brain serotonergic systems to a tryptophan deficient diet during three days and one or three weeks of ingestion. The concentrations of serotonin, noradrenaline, dopamine and their metabolites were measured in blood plasma, the hypothalamus and brain stem of male rats. The enzyme activity and protein levels in the liver were determined for isoforms CYP1A, CYP2A, CYP2B, CYP2C6, CYP2C11, CYP2D and CYP3A. A three-day tryptophan-free diet increased serotonin content in the hypothalamus (but not in the brain stem or plasma). After one week, the level of serotonin was not changed in the brain, but was markedly increased in the plasma. A three week tryptophan restriction significantly reduced the concentration of serotonin in the brain and plasma. Changes in CYP2C6 and CYP2C11 (an increase and a decrease, respectively) were maintained throughout the experiment, while those found in other CYP isoforms varied, which usually resulted in a gradual increase in the enzyme activity within three weeks. The observed alterations in liver CYPs suggest involvement of both central and peripheral serotonin in the regulation of liver CYP expression whose mechanism is discussed. In conclusion, a deficit in tryptophan in the diet may be responsible for very serious food-cytochrome P450 and food–drug metabolism interactions. Interactions of this type may also refer to drugs acting via serotonergic system.
FICZ, a Tryptophan photoproduct, suppresses pulmonary eosinophilia and Th2-type cytokine production in a mouse model of ovalbumin-induced allergic asthma
2012, International Immunopharmacology
Citation Excerpt :
In addition, UVB exposure of human skin induced CYP1A1 and CYP1B1 expression, raising a possibility that tryptophan photoproducts including FICZ are involved in AhR activation [43]. The rate of conversion from tryptophan to FICZ is about 0.0001% in cells and ex vitro [40,44] and the turnover rate is high with a decrease by 81% after 24 h of incubation [44]. At present, it remains to be seen how much of FICZ is produced in the skin exposed to UV and how relevant the results in this study is to asthma incidence in humans, because of differences in tryptophan metabolism among mammalian species [45,46].
Most studies about functions of aryl hydrocarbon receptor (AhR) in the pathogenesis of asthma have been carried out with non-physiological industrial by-products such as 2,3,7,8-tetrachlorodibenzo-p-dioxin and benzo(a)pyrene. In the present study, effects of 6-formylindolo[3,2-b]carbazole (FICZ), a tryptophan photoproduct postulated as a candidate physiological ligand of AhR, on the pathogenesis of asthma were examined and then underlying mechanisms of its immumodulatory effects were investigated. FICZ significantly reduced pulmonary eosinophilia and Th2 cytokine expression in the lungs. Flow cytometric analysis of mediastinal lymph nodes showed that IL-4 producing cells decreased in FICZ-treated mice compared with PBS control. Next, effects of FICZ on in vitro Th2 differentiation and expression of the Th2 transcription factor GATA-3 were examined. CD4 + T cells were isolated from the spleen and incubated under the Th2 differentiation conditions. FICZ inhibited both Th2 differentiation and the expression of GATA-3. Finally, activation of STAT6, which is necessary for Th2 differentiation, was inhibited by FICZ.

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¹: Present address: Genetica DNA Laboratories, Inc., 8740 Montgomery Road, Cincinnati, OH 45236, USA.

²: Present address: Analytical Pharmacology Laboratory, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.

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Discovery and biological characterization of 1-(1H-indol-3-yl)-9H-pyrido[3,4-b]indole as an aryl hydrocarbon receptor activator generated by photoactivation of tryptophan by sunlight

Abstract

Highlights

Introduction

Section snippets

Materials

Isolation of the main EROD inducing peaks in fraction 7 of 14 fractions collected from RP-HPLC separation of an aTRP solution exposed to sunlight for 7 days

Discussion

Conflict of interest statement

Acknowledgments

J. Biol. Chem.

J. Biol. Chem.

Chem. Biol. Interact.

Methods

J. Pharmacol. Toxicol. Methods

Tetrahedron Lett.

Tetrahedron Lett.

J. Biol. Chem.

Chemosphere

FEBS Lett.

J. Invest. Dermatol.

An introduction to the molecular basics of aryl hydrocarbon receptor biology

Biol. Chem.

Molecular mechanisms of the physiological functions of the aryl hydrocarbon (dioxin) receptor, a multifunctional regulator that senses and responds to environmental stimuli

Proc. Jpn. Acad. Ser. B Phys. Biol. Sci.

2, 3, 7, 8-tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity

Annu. Rev. Pharmacol. Toxicol.

Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals

Annu. Rev. Pharmacol. Toxicol.

Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation

Proc. Natl. Acad. Sci. USA