Some agonists appear to be curative agents operating systems AhR was regulating in the absence of exogenous dioxin-like compounds, synergizing with endogenous AhR regulation. Notice how THC interacts with the arylhydrocarbon hydroxylase. Those studies were never duplicated to test for endogenous cannabinoid similarities. Agonists would normally reduce cancer incidences. Antagonists will help after exposure to dioxins. Agonists that we know are in safe foods probably synergize with exogenous dioxins to cause cancer, whereas the antagonists were probably more harmful at one time. If endogenous cannabinoid activity mediates AhR activity, SNPs in genes in the endometabolome may be responsible for individual sensitivity to dioxin-like compounds and play a role in complicating procedure to restore health, converging at tryptophan 2,3-dioxygenase and B and T lymphocytes. 

Inhibitors: Cacao polyphenol, Molokhia, known as Egyptian spinach, Curcuma longa and curcumin, quercetin analogue flavonol-C-glucoside, kaempferol, ginkgo biloba, chrysophanol, danthron, rhein, aloe-emodin, apigenin, quercetin, anthraquinones such as emodin, Kampo formula Bakumondo-to: ophiopogonis tuber, pinelliae tuber, oryzae semen, zizyphi fructus, ginseng radix, glycyrhizzae radix. lutein and chlorophyll a and b from green tea leaves, EGCG, four theaflavins in black tea extract: theaflavin, theaflavin-3-gallate, theaflavin-3'-gallate, and theaflavin-3,3'-digallate, Siraitia grosvenorii (luo han guo) extract, proteasome inhibitors N-acetyl-leucyl-leucyl-norleucinal and lactacystin, flavone, flavonol, flavanone, catechol, melanin extracted from Thea sinensis reduced tea melanin and non-reduced, geranylgeranylacetone, vitamin A and vitamin E succinate, sage, spinach, citrus, piperine, coumestrol, brevifolincarboxylic acid, resveratrol, carnosol, capsaicin, ethanolic extracts of propolis and Baccharis dracunculifolia flavonoid aglycones, Artepillin C (3,5-diprenyl-4-hydroxycinnamic acid)

Activators: ginseng, Fo-Ti, white oak bark, licorice, ginkgo biloba, black cohosh, corn, jalapeño pepper, green bell pepper, apple, Brussels sprout, potato, 1,4-Dihydroxyanthraquinone (quinizarin), 1,5-dihydroxyanthraquinone (anthrarufin), 1,8-dihydroxyanthraquinone (danthron), and 5-hydroxy-1,4-naphthoquinone (juglone) daidzein, resveratrol (a stilbene) structure, some flavanones such as naringenin, and flavones such as baicalein, Prunella vulgaris, cigarette smoke extract, Cordyceps militaris, diesel exhaust particle, Aminoflavone, maltol 

Cacao polyphenol extract suppresses transformation of an aryl hydrocarbon receptor in C57BL/6 mice. Inhibiting the formation of a heterodimer between AhR and an aryl hydrocarbon receptor nuclear translocator in the liver. suppressed MC-induced cytochrome P4501A1 expression and NAD(P)H:quinone-oxidoreductase activity, whereas it increased glutathione S-transferase activity.  PMID: 18928297
The aryl hydrocarbon receptor (AhR) has dual roles in regulating intracellular protein levels both as a ligand-activated transcription factor and as a ligand-dependent E3 ubiquitin ligase. AhR E3 ubiquitin ligase has a role in suppression of intestinal carcinogenesis by a previously undescribed ligand-dependent beta-catenin degradation pathway. Activated by both xenobiotics and natural AhR ligands, such as indole derivatives that are converted from dietary tryptophan and glucosinolates by intestinal microbes, and suppresses intestinal tumor development  PMID: 19651607
Molokhia, known as Egyptian spinach, showed the strongest suppressive effect on AhR transformation among 41 kinds of extracts from vegetables and fruits. inhibiting translocation of the AhR from cytosol into the nucleus in the liver.  PMID: 16115717
Curcuma longa, did not inhibit the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced translocation of the AhR into the nucleus, but rather accelerated it. . In the nucleus, curcumin inhibited the TCDD-induced heterodimerization of the AhR with an AhR nuclear translocator (Arnt), an essential partner for the transformation, and also dose-dependently inhibited the TCDD-evoked phosphorylation of both the AhR and Arnt. curcumin significantly inhibited the TCDD-induced activation of protein kinase C (PKC), which is involved in the transformation, decreased the TCDD-induced DNA-binding activity of the AhR/Arnt heterodimer, and downregulated CYP1A1 expression. binds to the AhR as a ligand, but suppresses its transformation by inhibiting the phosphorylation of AhR and Arnt, probably by PKC. PMID: 17880909
A novel quercetin analogue from stem bark of Ulmus wallichiana promoted peak bone mass achievement. 6-C-β-D-glucopyranosyl-(2S,3S)-(+)-3',4',5,7-tetrahydroxyflavanol (GTDF), a novel flavonol-C-glucoside isolated from the extracts, had a nonestrogenic bone-sparing effect. GTDF stimulated osteoblast proliferation, survival, and differentiation. GTDF transactivated the aryl hydrocarbon receptor (AhR). Activation of AhR mediated the stimulatory effect of GTDF on osteoblast proliferation and differentiation. GTDF stimulated cAMP production, which mediated osteogenic gene expression. increased the mRNA levels of AhR target genes in calvaria or bone marrow stromal cells. PMID: 21638315
(ginseng, Fo-Ti, white oak bark, licorice, ginkgo biloba, and black cohosh) stimulated AhR DNA binding and gene expression to levels between 20 and 60% of that produced by TCDD. (corn, jalapeño pepper, green bell pepper, apple, Brussels sprout, and potato) were relatively potent activators of AhR DNA binding (30-50% of TCDD), only corn and jalapeño pepper extracts induced AhR-dependent luciferase reporter gene expression. dilution of corn, jalapeño pepper, bell pepper, and potato extracts dramatically increased their ability to induce luciferase activity, suggesting that these extracts contained AhR antagonists whose effectiveness was overcome by dilution. PMID: 12926901
kaempferol or ginkgo biloba extract (EGb) containing 24% flavonol at 100 mg/kg body weight suppressed AhR transformation induced by 3-methylcholanthrene at 10 mg/kg body weight in the liver. suppressive effect of kaempferol was enhanced by verapamil, an inhibitor of P-glycoprotein (P-gp). Enhancement of the suppressive effect by verapamil was also observed in mouse hepatoma Hepa-1c1c7 cells, accompanied by an increase in the uptake of kaempferol into the cells. inhibition of P-gp enhanced the suppressive effect of kaempferol on AhR transformation through an increase in the intracellular kaempferol concentration. PMID: 19584540
a known disruptor of B-cell differentiation, binding of the AhR to dioxin responsive elements (DRE) in sensitive genes. Ig heavy chain (IgH) gene is transcriptionally inhibited by TCDD through inhibition of the 3'IgH transcriptional regulatory region (3'IgHRR). AhR as an important regulator of IgH expression. inhibition of both 3'IgHRR activation and IgH protein expression by the non-dioxin AhR activators indolo(3,2-b)carbazole, primaquine, carbaryl, and omeprazole which followed a rank order potency for AhR activation supporting a role of the AhR in the transcriptional regulation of the 3'IgHRR and IgH expression. However, modulation of the 3'IgHRR and IgH expression was not limited to AhR activators or to suppressive effects. Hydrogen peroxide and terbutaline had an activating effect and benzyl isothiocyanate was inhibitory. These chemicals are not known to influence the AhR signaling pathway but have been previously shown to modulate humoral immunity and/or transcription factors that regulate the 3'IgHRR. PMID: 19447539
TCDD-induced inhibition of micro heavy chain expression and thus of IgM secretion. 3'alpha Ig heavy chain enhancer, which is composed of four regulatory domains that span approximately 40 kb. One of these domains, hs4, contains a DRE-like site that overlaps a kappaB motif. previously demonstrated TCDD-inducible binding of both the AhR nuclear complex and NF-kappaB/Rel proteins to the DRE and kappaB motifs, respectively, as well as TCDD and LPS-induced transcriptional activity through the hs4 domain. determine if the AhR nuclear complex and NF-kappaB/Rel proteins converge at these two overlapping cis-elements and act cooperatively to influence enhancer activity. TCDD activated the hs4 fragment; however, co-treatment with LPS led to a marked and synergistic activation. AhR nuclear complex and NF-kappaB/Rel proteins converge at the DRE and kappaB motif to influence transcriptional activity of the hs4 enhancer fragment. PMID: 15212819
1,4-Dihydroxyanthraquinone (quinizarin), 1,5-dihydroxyanthraquinone (anthrarufin), 1,8-dihydroxyanthraquinone (danthron), and 5-hydroxy-1,4-naphthoquinone (juglone) strongly suppressed DNA-binding activity of the AhR induced by 0.1 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), with their IC(50) values around 1 muM. hydroxyl groups at C1 or C4 but not C3 position of anthraquinone structure are critical for the suppressive effects. In human hepatoma HepG2 cells, chrysophanol, danthron, and rhein also suppressed the DNA-binding activity in a dose-dependent manner, although aloe-emodin showed a moderate effect. PMID: 19269596
marked AhR activation was exhibited by isoflavones such as daidzein, resveratrol (a stilbene) structure, some flavanones such as naringenin, and flavones such as baicalein. flavones such as apigenin, flavonols such as quercetin, and anthraquinones such as emodin, showed notable inhibitory effects. leafy green vegetables, citrus fruits, and herbs that contain food polyphenolics showed AhR-based interactions at high concentrations. PMID: 17869316
Prunella vulgaris (PV), a commonly used Chinese herb, also known as Self-heal displayed significant antiestrogenic activity. significantly reduced alkaline phosphatase activity and cell proliferation in response to estrogen in a dose-dependent manner. CYR61, an estrogen-induced protein, was blocked. not appear to directly inhibit estrogen signaling. Rather, we found that its activities were probably related to an ability to function as an aryl hydrocarbon receptor (AHR) agonist. PV induced CYP1A1, CYP1B1, and AHR repressor expression in a dose-dependent manner--responses that were blocked by small interfering RNA treatment to reduce AHR and specific AHR antagonists. immunohistochemistry demonstrated persistent estrogen receptor (ER), but reduced proliferation and CYR61 expression by PV tea treatment. ability of PV-activated AHR to interfere with estrogen. PMID: 18923163
four Kampo formulae (Bakumondo-to, Keigai-rengyo-to, Gosha-jinki-gan and Hochu-ekki-to) were administered to four representative dioxin and related organochlorine symptoms (respiratory, skin, neurological symptoms and general fatigue) for half a year. Bakumondo-to significantly improved respiratory symptoms. PMID: 19996156
lutein and chlorophyll a and b from green tea leaves as novel antagonists for AhR. suppressed AhR transformation dose-dependently with the 50% inhibitory concentration (IC(50)) values against 0.1 nM TCDD-induced AhR transformation at 3.2, 5.0, and 5.9 microM .EGCG, which is the most abundant flavonoid in green tea leaves, also showed stronger suppressive effects than did other major tea components, with the IC(50) value of 1.7 microM. through the suppression of AhR transformation. PMID: 15113147
black tea extract strongly suppressed AhR transformation compared to green and oolong tea, although the catechin contents did not change significantly among the extracts. four theaflavins as active compounds from black tea leaves. The IC(50) values of theaflavin, theaflavin-3-gallate, theaflavin-3'-gallate, and theaflavin-3,3'-digallate (Tfdg) were 4.5, 2.3, 2.2, and 0.7 muM, respectively. observed not only by pre-treatment but also by post-treatment. theaflavins inhibit the binding of TCDD to the AhR and also the binding of the transformed AhR to the specific DNA-binding site. PMID: 15914905
Siraitia grosvenorii extract inhibited the induction of gamma-glutamyltranspeptidase-positive hepatocytes, lipid peroxidation, and gene expression of Cyp1a1, all of which were caused by Dicyclanil. Cyp1a1 gene expression was significantly lower in mice administered DC + SGE. inhibited hepatocarcinogenesis, probably due to suppression of Ahr activity. PMID: 19182440
cigarette smoke extract markedly induced activation of AhR, inhibiting differentiation of preadipocytes into adipocytes with a decrease in lipid accumulation, blunted expression of adipocyte markers (adiponectin, PPAR-gamma, and C/EBPalpha), and sustained expression of a preadipocyte marker MCP-1. CSE induced ER stress in preadipocytes. Interestingly, AhR agonists did not cause ER stress, and ER stress inducers did not activate AhR. cigarette smoke has the potential to inhibit adipocyte differentiation via dual, independent mechanisms, i.e., through activation of the AhR pathway and induction of the unfolded protein response. PMID: 19141685
inducible expression of the reporter in T47D breast tumor cells with AhR ligands was significantly reduced by co-treatment with N-acetyl-leucyl-leucyl-norleucinal. the induced expression of CYP1A1 and CYP1B1 mRNAs was unaffected by ALLN. lactacystin, another proteasome inhibitor, exhibited the same effect as ALLN on reporter activity induced by AhR ligands. proteasome inhibition results in a reduction in the expression of AhR-regulated proteins. PMID: 21791387
antiadipogenic mycelia Cordyceps militaris suppressed differentiation of 3T3-L1 preadipocytes into mature adipocytes without affecting cell viability. associated with 1) a decrease in lipid accumulation, 2) blunted induction of adipocyte markers including adiponectin, peroxisome proliferator-activated receptor-gamma, and CCAAT/enhancer binding protein-alpha, and 3) sustained expression of a preadipocyte marker, monocyte chemoattractant protein-1. decreased accumulation of lipid and hypertrophy in mature adipocytes and preserved their response to insulin (phosphorylation of Akt). C. militaris has the potential to activate the aryl hydrocarbon receptor (AhR). C. militaris has the potential to interfere with adipocyte differentiation through activation of AhR. PMID: 18664595
Flavone, flavonol, and flavanone but not catechin inhibited the specific binding between the AhR and 3-methylcholanthrene dose-dependently, indicating that the former three subclasses possibly act as competitive antagonists of the AhR. However, catechin in addition to the former three subclasses directly interacted with the AhRc by surface plasmon resonance analysis. dissociation constant values showed an inverse correlation with the suppressive effect on the DNA binding activity. flavone, flavonol, and flavanone act as competitive antagonists of the AhR, while catechin associates with the AhRc and indirectly exhibits its antagonistic effects. PMID: 17560542
Reduced tea melanin (RTM) and non-reduced tea melanin (NRTM). RTM protected the animals against TCDD-induced lipid peroxidation, inhibition of glutathione peroxidase, alteration in reduced and oxidized glutathione concentrations, loss of body weight, and increased relative liver weight. NRTM was less effective as compared to RTM because of its inferior antioxidant activity, but it still displayed a strong protective effect against TCDD toxicity owing to its similar suppression of the activity of the aryl hydrocarbon receptor. Both NRTM and RTM suppressed the expression of CYP1A1 gene and prevented the activation of cytochrome P450 isozyme in the livers. dual protection against the development of TCDD-induced oxidative stress. PMID:17077530
melanin extracted from Thea sinensis Linn. antagonistic activity against different venoms. MEBT demonstrated neutralization effect against all venoms tested at dose of 3 mg. PMID: 14967198
Mitochondrial reactive oxygen production is dependent on the aromatic hydrocarbon receptor. dioxin caused a rise in succinate-stimulated mitochondrial H(2)O(2) production. Dioxin decreased mitochondrial aconitase (an enzyme inactivated by superoxide) by 44%. Dioxin treatment increased mitochondrial glutathione levels. These results suggest that both constitutive and dioxin-induced mitochondrial reactive oxygen production is associated with a function of the AHR, and these effects are independent of either CYP1A1 or CYP1A2. PMID: 12398935
Geranylgeranylacetone (GGA), an antiulcer drug, counteracts suppression of body weight gain and lethality produced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). curcumin, a food ingredient anticipates the TCDD's toxicity on body weight gain. Both GGA and curcumin had no effect on the induction of hepatic ethoxyresorufin O-deethylase activity by TCDD. These data suggest that both compounds exhibit a protective effect against some forms of dioxin toxicity by a mechanism without involving inhibition of aryl hydrocarbon receptor activation. PMID: 15997774
Low-dose dioxins alter gene expression related to cholesterol biosynthesis, lipogenesis, and glucose metabolism. Changes in the expression of genes involved in the circadian rhythm, cholesterol biosynthesis, fatty acid synthesis, and glucose metabolism in the liver even at 5 ng/kg for 18 days. affect energy metabolism via alterations of gene expression. PMID: 18295293
vitamin A and TCDD or vitamin E succinate exhibited reduction in indicators of acute toxicity including the decrease in total body and thymus weight. also a significant reduction in the increase in liver weight as compared to TCDD only. Following one day of treatment with 50 microg TCDD/kg, vitamin A and vitamin E succinate produced a significant decrease in the production of superoxide anion by peritoneal lavage cells (P<0.05) and in DNA-single strand breaks. A significant decrease in DNA-single strand breaks in peritoneal lavage cells was observed following 5 days treatment with 50 microg TCDD/kg. PMID: 15447737
In concert with reduced body weight, TCDD increased brain TRP concentration, 5-HT synthesis and its metabolism to 5-HIAA at lethal doses in TCDD-susceptible L-E rats, and almost not at all in resistant H/W rats. TCDD indirectly increases free TRP concentration in the circulation in TCDD-susceptible L-E rats. Blood free fatty acids seem to be involved. not likely that the enhanced serotonergic tone in the CNS is a causative factor in TCDD-induced anorexia. However, the present results may open up an interesting avenue to better understand physiology of TRP and the complex regulation of energy balance. PMID: 10721086
dose-related increase in brain 5-HT turnover and plasma free tryptophan. Nonesterified fatty acids (NEFA) in the plasma were dose dependently elevated in male and female L-E rats and there was a moderate or good correlation (r = 0.654 for male and r = 0.731 for female rats) between this parameter and plasma free tryptophan. Bilirubin was dose dependently increased in the plasma of female L-E rats and there was a good correlation between plasma free tryptophan and total (r = 0.779) or conjugated (r = 0.825) bilirubin. The concentration of albumin tended to be suppressed in female L-E rats. The main tryptophan metabolizing enzyme, hepatic tryptophan pyrrolase, was inhibited in female L-E rats but not in male L-E rats. PMID: 7940543
extracts of sage, among the vegetables, green leafy ones such as spinach, and among the fruit, citrus showed inhibitory effects on AhR activation by TCDD, although some tested samples did not show parallel behavior in both assays. Sage had a remarkable inhibitory effect (79% in the CALUX assay and 83% in the Ah-Immunoassay compared with control) and its effects were dose dependent. PMID: 11853182
Ninety vegetable constituents including flavonoids, tannins, saponins, terpenes, etc., were assayed in vitro. Among them, flavones, flavonols, anthraquinones, piperine, coumestrol, brevifolincarboxylic acid, and resveratrol showed marked inhibitory effects on AhR-based bioassay activation by TCDD, and their effects were dose dependent. Curcumin, carnosol, and capsaicin also inhibited the activation of AhR in this assay, although to a lesser degree. PMID: 14646185
ethanolic extracts of propolis containing higher concentrations of flavonoids suppressed 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced aryl hydrocarbon receptor transformation in a dose-dependent manner. The IC(50) values of propolis group 3 and group 12 were 1.2 and 3.6 microg/ml, respectively, indicating that propolis showed stronger antagonistic effects as compared with vegetable extracts. PMID: 15118327
its main botanical origin (leaf bud of Baccharis dracunculifolia). suppressive effects of propolis on AhR transformation were relatively higher than those of resins of its botanical origin. propolis contained slightly higher amounts of flavonoid aglycones as compared with its botanical origin with the same characteristics. antiradical activity, one of the typical biological activities of flavonoids, in propolis was also slightly higher than that in its botanical origin. not only propolis but also its botanical origin contains high amounts of flavonoid aglycones and that both of them are useful dietary sources for flavonoids with a potency to prevent dioxin toxicity. PMID: 16366731
Artepillin C (3,5-diprenyl-4-hydroxycinnamic acid) was also identified in both propolis and resinous exudates, and both ethanolic extracts contained the highest concentrations of this compound as compared with the rest of the chemical constituents. PMID: 14995105
delta9-THC completely suppressed the induction of arylhydrocarbon hydroxylase activity of 3-methylcholanthrene  from 455% to 177% of control. delta9-THC also inhibited the induction of aminopyrine demethylase by phenobarbital. These drugs do not have any interactive effect on microsomal protein synthesis but are potent antagonists in the synthesis of nuclear RNA. PMID: 996365
After ex vivo exposure to TCDD (a highly potent AhR ligand) for 3 h, Cyp1b1 expression was significantly increased by 2.3-fold in brain microvessels. A single i.p. dose of TCDD also increased Cyp1b1 transcripts (22-fold) and Cyp1b1 protein (2-fold) in rat brain microvessels at 72 h after TCDD. Likewise, DEP treatment (in vivo and ex vivo) strongly induced Cyp1b1 protein in brain microvessels. Diesel exhaust particle-mediated Cyp1b1 induction was inhibited by actinomycin D, cycloheximide, or by an AhR antagonist. In contrast, a sub-chronic in vivo treatment with Δ9-THC once daily for 7 seven days had no effect on Cyp1b1 expression. PMID: 21867498
CBD most potently inhibited catalytic activity of human CYP3A enzymes, especially CYP3A4 and CYP3A5. These results suggest that two phenolic hydroxyl groups in the resorcinol moiety of CBD may play an important role in the CYP3A inhibition. Olivetol partially inhibited all the CYP3A isoforms tested. two phenolic hydroxyl groups in the resorcinol moiety of CBD may play an important role in the CYP3A inhibition. PMID: 21356216
cdc42 expression was increased in comparison to the control cell line. exogenous AhR induced catecholaminergic differentiation. excessive activation of AhR resulted in neural differentiation of Neuro2a cells. This result revealed that dioxins may affect the nervous system through the AhR-signaling pathway. Activated AhR may disrupt the strictly regulated brain formation with irregular differentiation occurring rather than cell death. PMID: 16956419
Induction of TH by TCDD through AhR activation was detected at mRNA and protein levels. Induced TH protein was functional and its expression increased dopamine synthesis. AhR directly regulated TH gene expression. Regulatory sequence called aryl hydrocarbon receptor responsive element III (AHRE-III) was identified upstream of the TH gene from -285 bp to -167 bp. Under TCDD exposure, an AhR complex was bound to AHRE-III as well as the xenobiotic response element (XRE). TCDD directly regulate the dopamine system by TH gene transactivation via an AhR-AHRE-III-mediated pathway. The AhR- mediated pathway could have a particular AhR-mediated genomic control pathway transmitting the effects of TCDD action to target cells in the development of dopaminergic disabilities. PMID: 19500377
Endothelial cells are a target of halogenated aromatic hydrocarbon toxicity. AHR has a physiological function in endothelial cells in the absence of exogenous ligands. crosstalk between hypoxia and AHR in the absence of exogenous ligands. human pulmonary microvascular endothelial cells exposed to hypoxia (1 or 2.5% O2), 25 nM AHR siRNA, 25 nM hypoxia-inducible factor (HIF)-2alpha siRNA, or their combinations. Hypoxia significantly induced known hypoxia-regulated genes, and this induction was highly attenuated by HIF-2alpha siRNA. Hypoxia also significantly reduced CYP1A1 mRNA and this reduction was also attenuated by HIF-2alpha siRNA. As expected, AHR siRNA significantly reduced constitutive CYP1A1 mRNA. While the combination of hypoxia plus AHR siRNA reduced CYP1A1 mRNA more than either treatment alone, the reduction was less than additive, suggesting that hypoxia and AHR deficiency may share a common pathway in reducing CYP1A1 expression. hypoxia significantly reduced AHR mRNA and this reduction was completely prevented by HIF-2alpha siRNA. constitutive CYP1A1 mRNA expression is dependent on AHR and is reduced by hypoxia via a HIF-2alpha-dependent mechanism, which may be mediated by a HIF-2alpha-dependent reduction of AHR expression. PMID: 17968679
AhR antagonist resveratrol (RSV) could reverse this TCDD-induced CYP1A1 expression. both MMP-9 mRNA expression and enzymatic activity were gradually increased with the concentration increase of TCDD in media and these changes could be reversed by RSV treatment in a dose-dependent manner. After TCDD treatment, the migration distance and the migration and invasion abilities of human gastric cancer AGS cells were increased with a dose-dependent manner.  MMP-9 mRNA expression and activity in untreated control AGS cells were very weak; After TCDD (10 nmol/L) treatment, MMP-9 mRNA expression and activity were significant increased; This TCDD-induced MMP-9 expression and activity increase could be abolished by c-Jun siRNA transfection. Aryl hydrocarbon receptor pathway activation enhances gastric cancer cell invasiveness likely through a c-Jun-dependent induction of matrix metalloproteinase-9. PMID: 19371443
Aminoflavone (AF), the active component of a novel anticancer agent (AFP464) in phase I clinical trials, is a ligand of the aryl hydrocarbon receptor (AhR). AhR dimerizes with HIF-1beta/AhR, which is shared with HIF-1alpha, a transcription factor critical for the response of cells to oxygen deprivation. To address whether pharmacologic activation of the AhR pathway might be a potential mechanism for inhibition of HIF-1, we tested the effects of AF on HIF-1 expression. AF inhibited HIF-1alpha transcriptional activity and protein accumulation in MCF-7 cells. However, inhibition of HIF-1alpha by AF was independent from a functional AhR pathway. Indeed, AF inhibited HIF-1alpha expression in Ah(R100) cells, in which the AhR pathway is functionally impaired, yet did not induce cytotoxicity, providing evidence that these effects are mediated by distinct signaling pathways. AF was inactive in MDA-MB-231 cells, yet inhibited HIF-1alpha in MDA-MB-231 cells transfected with the SULT1A1 gene. AF inhibited HIF-1alpha mRNA expression by approximately 50%. Notably, actinomycin-D completely abrogated the ability of AF to downregulate HIF-1alpha mRNA, indicating that active transcription was required for the inhibition of HIF-1alpha expression. AF inhibited HIF-1alpha protein accumulation and the expression of HIF-1 target genes in MCF-7 xenografts. AF inhibits HIF-1alpha in an AhR-independent fashion. PMID: 20736373
Cockayne Syndrome group B (CSB) mutant cells are unable to react to hypoxic stimuli by properly activating the hypoxia-inducible factor-1 (HIF-1) pathway, a defect that is further enhanced in the event of a concomitant genotoxic stress. CSB expression is under the control of HIF-1 and has a critical function during hypoxic response by redistributing p300 between HIF-1 and p53. CSB is part of a feedback loop mechanism that modulates the biological functions of p53. PMID: 18784753
intestinal bacteria may contribute to induce inflammation in individuals afflicted by inflammatory bowel disease (IBD), increasing the risk of developing colon cancer. Accumulating evidence suggests that Helicobacter organisms are linked to IBD as well as to gastric and colon cancer. evaluate the effect of lipopolysaccharide (LPS) isolated from Helicobacter on modulating the DNA repair system. We used an in vitro model represented by two colon carcinoma cell lines, the DNA repair-proficient SW480 and the DNA repair-deficient LoVo, and transfected with a UVC-irradiated psV-beta-galactosidase plasmid. We observed that LPS, by upregulating the expression of inducible nitric oxide (NO), leads to an increased NO release, demonstrating that LPS is able to interfere with the DNA repair machinery of intestinal cells, thus increasing the risk of permanent genotoxic effects. PMID: 19651607
treatment of Hepa 1c1c7 cells with maltol significantly induced Cyp1a1 at mRNA, protein, and activity levels in a concentration-dependent manner. The RNA synthesis inhibitor, actinomycin D, completely blocked the Cyp1a1 mRNA induction by maltol, indicating a requirement of de novo RNA synthesis through transcriptional activation. In addition, maltol induced aryl hydrocarbon receptor (AhR)-dependent luciferase reporter gene expression in stably transfected H1L1.1c2 cells, suggesting an AhR-dependent mechanism. This is the first demonstration that the food flavoring agent, maltol, can directly induce Cyp1a1 gene expression in an AhR-dependent manner and represents a novel mechanism by which maltol promotes carcinogenicity and toxicity. PMID: 17317091
Ginkgo biloba extract (GBE) had the strongest inhibitory effect on DEP-induced AhR activation. Quercetin, a major polyphenol in onions, and GBE showed a strong inhibitory effect. PMID: 17622219