Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CYP1A1 and 1A2 play critical roles in the metabolic activation of carcinogenic polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines/amides (HAAs), respectively, to electrophilic reactive intermediates, leading to toxicity and cancer. CYP1As are highly inducible by PAHs and halogenated aromatic hydrocarbons via aryl hydrocarbon receptor-mediated gene transcription. The impact of CYP1A induction on the carcinogenic and toxic potentials of environmental, occupational, dietary, and therapeutic chemicals has been a central focus of human risk evaluation and has broadly influenced the fields of cancer research, toxicology, pharmacology, and risk assessment over the past half-century. From the early discovery of CYP1A induction and its role in protection against chemical carcinogenesis in intact animals, to the establishment of CYP1A enzymes as the principal cytochromes P450 for bioactivation of PAHs and HAAs in in vitro assays, to the recent realization of an essential protective role of CYP1A in benzo[a]pyrene-induced lethality and carcinogenesis with CYP1A knockout mice, the understanding of the interrelation between CYP1A induction and chemical safety has followed a full circle. This unique path of CYP1A research underscores the importance of whole animal and human studies in chemical safety evaluation.
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PMID:CYP1A induction and human risk assessment: an evolving tale of in vitro and in vivo studies. 1743 Oct 34

Various liver diseases lead to an extensive inflammatory response and release of a number of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha). This cytokine is known to play a major role in liver regeneration as well as in carcinogenesis. We investigated possible interactions of TNF-alpha with ligands of the aryl hydrocarbon receptor (AhR) and known liver carcinogens, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and coplanar 3,3',4,4',5-pentachlorobiphenyl (PCB 126). These compounds have been previously found to disrupt cell cycle control in contact-inhibited rat liver WB-F344 cells, an in vitro model of adult liver progenitor cells. TNF-alpha itself had no significant effect on the proliferation/apoptosis ratio in the WB-F344 cell line. However, it significantly potentiated proliferative effects of low picomolar range doses of both TCDD and PCB 126, leading to an increase in cell numbers, as well as an increased percentage of cells entering the S-phase of the cell cycle. The combination of TNF-alpha with low concentrations of AhR ligands increased both messenger RNA (mRNA) and protein levels of cyclin A, a principle cyclin involved in disruption of contact inhibition. TNF-alpha temporarily inhibited AhR-dependent induction of cytochrome P450 1A1 (CYP1A1). In contrast, TNF-alpha significantly enhanced induction of CYP1B1 at both mRNA and protein levels, by a mechanism, which was independent of nuclear factor-kappaB activation. These results suggest that TNF-alpha can significantly amplify effects of AhR ligands on deregulation of cell proliferation control, as well as on expression of CYP1B1, which is involved in metabolic activation of a number of mutagenic compounds.
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PMID:Tumor necrosis factor-alpha modulates effects of aryl hydrocarbon receptor ligands on cell proliferation and expression of cytochrome P450 enzymes in rat liver "stem-like" cells. 1755 10

4-Methoxyequilenin (4-MeOEN) is an O-methylated metabolite in equine estrogen metabolism. O-methylation of catechol estrogens is considered as a protective mechanism; however, comparison of the properties of 4-MeOEN with estradiol (E(2)) in human breast cancer cells showed that 4-MeOEN is a proliferative, estrogenic agent that may contribute to carcinogenesis. 4-MeOEN results from O-methylation of 4-hydroxyequilenin, a major catechol metabolite of the equine estrogens present in hormone replacement therapeutics, which causes DNA damage via quinone formation, raising the possibility of synergistic hormonal and chemical carcinogenesis. 4-MeOEN induced cell proliferation with nanomolar potency and induced estrogen response element (ERE)-mediated gene transcription of an ERE-luciferase reporter and the endogenous estrogen-responsive genes pS2 and TGF-alpha. These estrogenic actions were blocked by the antiestrogen ICI 182,780. In the standard radioligand estrogen receptor (ER) binding assay, 4-MeOEN showed very weak binding. To test for alternate ligand-ER-independent mechanisms, the possibility of aryl hydrocarbon receptor (AhR) binding and ER-AhR cross talk was examined using a xenobiotic response element-luciferase reporter and using AhR small interfering RNA silencing in the ERE-luciferase reporter assay. The results negated the possibility of AhR-mediated estrogenic activity. Comparison of gene transcription time course, ER degradation, and rapid activation of MAPK/ERK in MCF-7 cells demonstrated that the actions of 4-MeOEN mirrored those of E(2) with potency for classical and nonclassical estrogenic pathways bracketing that of E(2). Methylation of 4-OHEN may not represent a detoxification pathway because 4-MeOEN is a full, potent estrogen agonist.
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PMID:Activation of estrogen receptor-mediated gene transcription by the equine estrogen metabolite, 4-methoxyequilenin, in human breast cancer cells. 1758 65

The aryl hydrocarbon receptor (AhR) is a cytosolic ligand-activated transcription factor that mediates most of the toxic and carcinogenic effects of drugs and environmental toxins collectively known as xenobiotics. Ligand activation of the AhR stimulates the transcription of genes that encode several xenobiotic-metabolizing enzymes. The molecular mechanisms and signaling pathways evoked by the activation of the AhR are becoming increasingly understood and underscore the participation of the AhR in crucial processes, including cellular stress response, proliferation, differentiation, inflammation, and carcinogenesis. Studies now implicate the AhR as an integral part of the multifaceted signal transduction pathway initiated by the exposure of keratinocytes to ultraviolet B radiation (UVB), which is the most ubiquitous hazard to human skin and the principal risk factor for skin cancer. Ligand-dependent activation of the AhR in the cytosol provides a molecular bridge that links cytoplasmic events to nuclear signals, thus unmasking a previously unknown role for this transcription factor in the complex cellular response to UVB.
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PMID:The Aryl hydrocarbon receptor: an illuminating effector of the UVB response. 1784 86

Estrogenic status is thought to influence the cancer risk in women and has been reported to affect toxicity of carcinogenic polycyclic aromatic hydrocarbons (PAHs) in animals. The objective of this study was to examine the influence of estradiol (E2) on hepatic gene expression changes mediated by 7,12-dimethylbenz(a)anthracene (DMBA), a potent PAH. Sprague-Dawley rats were ovariectomized on postnatal day 50 and infused with E2 (5 mug/kg/day) or polyethylene glycol using osmotic pumps and 14 days later gavaged with DMBA (50 mg/kg) or sesame oil and killed 24 h thereafter. To understand the mechanism of DMBA-mediated hepatocarcinogenicity in the presence of E2, microarray analysis (Rat 230 2.0 Affymetrix-GeneChip) was performed. Two hundred and sixteen genes were downregulated; whereas, 106 genes were upregulated significantly (+/-1.5-fold, P < 0.05) by DMBA treatment. Hierarchical clustering revealed that the expression profile of 39 genes, regulated by DMBA, was significantly modified by E2 supplementation. Interestingly, 71 genes were uniquely modulated in the combined treatment of DMBA and E2, but not by either treatment alone. Results from chromatin immunoprecipitation assay demonstrate that in animals cotreated with E2 and DMBA, there was enhanced recruitment of estrogen receptor-alpha to the regulatory regions of CYP1A1 and aryl hydrocarbon receptor (AhR) genes compared with that observed in animals treated with DMBA alone. E2 supplementation leads to increased DMBA-induced CYP1A1 transcription, while the AhR gene was upregulated in the presence of E2 +DMBA only. Our data suggest that estrogenic status is (i) important in AhR regulation and can influence the effects of xenobiotics and (ii) may be an important factor in DMBA-mediated carcinogenicity.
Carcinogenesis 2008 Feb
PMID:Estrogenic status modulates aryl hydrocarbon receptor--mediated hepatic gene expression and carcinogenicity. 1817 42

Curcumin has been shown to possess anti-initiating and anti-promoting activity in experimental systems. However, the mechanisms of its actions are not fully elucidated in vivo. In the present study, mechanisms of curcumin-mediated anti-initiation were investigated in mice employing benzo[a]pyrene (B[a]P) as a model carcinogen. Dietary pretreatment of mice with chemopreventive doses of curcumin showed significant inhibition of B[a]P-induced enzyme activity, protein and messenger RNA (mRNA) levels of cytochrome P450 1A1/1A2 in liver and lungs. Although curcumin alone did not alter the basal levels of aryl hydrocarbon receptor (AhR), it significantly decreased the B[a]P-induced AhR protein levels, its phosphorylation, nuclear translocation and subsequent binding to DNA, thereby decreasing the transactivation of CYP1A. Dietary curcumin led to increase in NF-E2-related factor-2 (Nrf2) protein levels and enhanced its nuclear translocation in liver and lungs of mice as compared with controls. Additionally, increased binding of Nrf2 to antioxidant response element occurred in nuclear extracts from liver and lungs of mice pretreated with dietary curcumin. Induction of activity, protein and mRNA levels of glutathione S-transferase, its isoforms and NAD(P)H:quinone oxidoreductase-1 by dietary curcumin in mice paralleled the curcumin-mediated activation of Nrf2, leading to increased detoxification of B[a]P. In agreement with the observed curcumin-mediated decrease in B[a]P-induced phase I enzyme and concomitant induction of phase II enzymes, pretreatment with dietary curcumin resulted in significant reduction of B[a]P-induced DNA adduct, oxidative damage and inflammation. To conclude, curcumin exhibits anti-initiating effects via modulating the transcriptional regulators of phase I and phase II enzymes in mice.
Carcinogenesis 2008 May
PMID:Dietary curcumin modulates transcriptional regulators of phase I and phase II enzymes in benzo[a]pyrene-treated mice: mechanism of its anti-initiating action. 1832 68

Hypoxia-inducible factor-1 alpha (HIF-1alpha) and aryl hydrocarbon receptor nuclear translocator (ARNT) are basic helix-loop-helix/per-arnt-sim (PAS) family transcription factors. During angiogenesis and tumor growth, HIF-1alpha dimerizes with ARNT, inducing expression of many genes, including vascular endothelial growth factor (VEGF). ARNT also dimerizes with the aryl hydrocarbon receptor (AhR). AhR-null (Ahr(-/-)) transgenic adenocarcinoma of the mouse prostate (TRAMP) mice develop prostate tumors with greater frequency than AhR wild-type (Ahr(+/+)) TRAMP mice, even though prevalence of prostate epithelial hyperplasia is not inhibited. This suggests that Ahr inhibits prostate carcinogenesis. In TRAMP mice, prostatic epithelial hyperplasia results in stabilized HIF-1alpha, inducing expression of VEGF, a prerequisite for tumor growth and angiogenesis. Since ARNT is a common dimerization partner of AhR and HIF-1alpha, we hypothesized that the AhR inhibits prostate tumor formation by competing with HIF-1alpha for ARNT, thereby limiting VEGF production. Prostates from Ahr(+/+), Ahr(+/-) and Ahr(-/-) C57BL/6J TRAMP mice were cultured in the presence of graded concentrations of vanadate, an inducer of VEGF through the HIF-1alpha-ARNT pathway. Vanadate induced VEGF protein in a dose-dependent fashion in Ahr(+/-) and Ahr(-/-) TRAMP cultures, but not in Ahr(+/+) cultures. However, vanadate induced upstream proteins in the phosphatidylinositol 3-kinase-signaling cascade to a similar extent in TRAMPs of each Ahr genotype, evidenced by v-akt murine thymoma viral oncogene homolog (Akt) phosphorylation. These findings suggest that AhR sequesters ARNT, decreasing interaction with HIF-1alpha reducing VEGF production. Since VEGF is required for tumor vascularization and growth, these studies further suggest that reduction in VEGF correlates with inhibited prostate carcinogenesis in Ahr(+/+) TRAMP mice.
Carcinogenesis 2008 May
PMID:The aryl hydrocarbon receptor (AhR) inhibits vanadate-induced vascular endothelial growth factor (VEGF) production in TRAMP prostates. 1835 62

Quercetin is an anti-oxidative flavonoid widely distributed in the plant kingdom. Phenolic hydroxyl groups at the B-ring and the 3-position are responsible for its free radical-scavenging activity. Quercetin is commonly present as a glycoside and is converted to glucuronide/sulfate conjugates during intestinal absorption and only conjugated metabolites are therefore found in circulating blood. Although metabolic conversion attenuates its biological effects, active aglycone may be generated from the glucuronide conjugates by enhanced beta-glucuronidase activity during inflammation. With respect to its relationship with molecular targets relevant to cancer prevention, quercetin aglycone has been shown to interact with some receptors, particularly an aryl hydrocarbon receptor, which is involved in the development of cancers induced by certain chemicals. Quercetin aglycone has also been shown to modulate several signal transduction pathways involving MEK/ERK and Nrf2/keap1, which are associated with the processes of inflammation and carcinogenesis. Rodent studies have demonstrated that dietary administration of this flavonol prevents chemically induced carcinogenesis, especially in the colon, whilst epidemiological studies have indicated that an intake of quercetin may be associated with the prevention of lung cancer. Dietary quercetin is, therefore, a promising agent for cancer prevention and further research is warranted.
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PMID:Multitargeted cancer prevention by quercetin. 1846 24

Polycyclic aromatic hydrocarbons (PAHs) are generated during smoke curing and other heating treatments of food and represent a large class of chemical pollutants including a number of carcinogens. At present, PAHs are frequently detected by costly and time-consuming chemical analysis. Effect-directed in vitro cell-based bioassays of contaminants can offer a rapid, sensitive, and relatively inexpensive alternative for screening of contaminants in comparison to instrumental analysis. They enable estimation of total biological activity of all compounds acting through the same mode of binding. The aryl hydrocarbon receptor as a binding site plays an important role in PAH-induced carcinogenesis. The in vitro chemical-activated luciferase expression assay (using conditions to detect PAH) was investigated for its applicability for effect-directed analysis of PAH levels in smoked meat. There was an intra-assay variability of 0 to 15% and a mean coefficient of variation of 25% (3 to 50%) for the cleanup and bioassay analysis of the smoked pork samples. There was a correlation between the total responses of the bioassay and the individual amounts of the PAHs with a high molecular weight. The comparison of 2,3,7,8-tetrachlorodibenzo-p-dioxin and benzo[k]fluoranthene used as standard in the in vitro chemical-activated luciferase expression assay resulted in benzo[k]fluoranthene being able to be used as an alternative, nontoxic standard in the bioassay. This bioassay is an applicable effect-directed functional prescreening method for the analysis of PAHs in smoked meat and appears to have potential in being used for food control in the future.
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PMID:Determination of polycyclic aromatic hydrocarbons in smoked pork by effect-directed bioassay with confirmation by chemical analysis. 1852 35

Polycyclic aromatic hydrocarbons (PAH) in coke oven emissions could cause lung cancer in human. Individual's genotype of the metabolic enzymes and early biological changes were known to be associated with the susceptibility of cancer development. Knowledge of metabolic gene polymorphisms, which affect on the urinary 1-hydroxypyrene (1-OHP), could benefit us in understanding the interindividual difference in the mechanism of PAH-induced carcinogenesis. In this study, we investigated the association of aryl hydrocarbon receptor (AhR) gene polymorphisms and urinary 1-OHP. One hundred forty-seven workers exposed to PAH and 69 nonexposure workers were recruited. Seven tagging single nucleotide polymorphisms in AhR gene were selected by pariwise r(2) method and minor allele frequency cutoff of 0.05 from Chinese genotype data in HapMap project. These seven tagging single nucleotide polymorphisms were genotyped by PCR-based methods. Multivariate analysis of covariance revealed that the levels of 1-OHP in PAH-exposed workers carrying genotype CT were lower than workers carrying wild genotype TT at loci rs10250822 and rs2282885 of AhR gene (P = 0.032 and 0.044, respectively). In PAH-exposed workers, the urinary 1-OHP levels showed a linear correlation (P(trend) = 0.041) with the genotypes at locus rs2282885, especially in low and moderate exposure groups. In contrast, no significant association was found between urinary 1-OHP level and AhR genotypes among nonexposed workers. Our findings indicated that polymorphisms of AhR gene were associated with the level of 1-OHP among PAH-exposed workers, suggesting that AhR-mediated signaling might contribute to individual susceptibility to PAH exposure.
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PMID:Association of aryl hydrocarbon receptor gene polymorphisms and urinary 1-hydroxypyrene in polycyclic aromatic hydrocarbon-exposed workers. 1862 20


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