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)

Risk assessment of dioxins is currently based on induction of liver tumors in rats. The toxicity of dioxins is characterized by large sensitivity differences among animal species and even strains of the same species, which complicates the risk assessment. The significance of these differences in dioxin-induced carcinogenicity is not known. We therefore studied the liver tumor-promoting activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the sensitive Long-Evans (L-E) and the resistant Han/Wistar (H/W) rats differing >1000-fold in their sensitivity to the acute lethaity of TCDD. Female rats were partially hepatectomized, initiated with nitrosodiethylamine, and treated with TCDD for 20 weeks. Altered hepatic foci (AHF) were stereologically quantitated using glutathione S-transferase P as a marker. AHF were significantly (P < 0.001) and dose dependently increased in L-E rats at 10 and 100 ng/kg/day, but in H/W rats only at 1000 ng/kg/day and above, indicating a remarkable (approximately 100-fold) sensitivity difference between L-E and H/W rats. The same sensitivity difference but 10-fold less foci were observed between nonhepatectomized/noninitiated L-E and H/W rats. Induction of AHF was related to hepatotoxicity but not to cytochrome P4501A1 activity in the liver. Liver TCDD concentrations were similar in both strains. H/W rats are exceptionally resistant to induction of AHF by TCDD, and the resistance is associated with an altered transactivation domain of the aryl hydrocarbon receptor. Genetic differences may account for significant interindividual/intraspecies sensitivity differences in dioxin-induced carcinogenesis. Understanding the role of transactivation domain of the aryl hydrocarbon receptor in carcinogenesis is therefore likely to improve dioxin risk assessment.
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PMID:Liver tumor-promoting activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in TCDD-sensitive and TCDD-resistant rat strains. 1115 90

Cytochrome P450 1B1 (CYP1B1) is a recently cloned dioxin-inducible form of the cytochrome P450 supergene family of xenobiotic-metabolizing enzymes. CYP1B1 is constitutively expressed mainly in extrahepatic tissues and is inducible by aryl hydrocarbon receptor ligands. Human CYP1B1 is involved in activation of chemically diverse human procarcinogens, including polycyclic aromatic hydrocarbons and some aromatic amines, as well as the endogenous hormone 17 beta-estradiol. The metabolism of 17 beta-estradiol by CYP1B1 forms 4-hydroxyestradiol, a product believed to be important in estrogen-induced carcinogenesis. Although the distribution of CYP1B1 mRNA and protein in a number of human normal tissues has been well documented, neither the cells expressing CYP1B1 in individual tissue nor the intracellular localization of the enzyme has been thoroughly characterized. In this study, using nonradioactive in situ hybridization and immunohistochemistry, we examined the cellular localization of CYP1B1 mRNA and protein in a range of human normal tissues. CYP1B1 mRNA and protein were expressed in most samples of parenchymal and stromal tissue from brain, kidney, prostate, breast, cervix, uterus, ovary, and lymph nodes. In most tissues, CYP1B1 immunostaining was nuclear. However, in tubule cells of kidney and secretory cells of mammary gland, immunoreactivity for CYP1B1 protein was found in both nucleus and cytoplasm. This study demonstrates for the first time the nuclear localization of CYP1B1 protein. Moreover, the constitutive expression and wide distribution of CYP1B1 mRNA and protein in many human normal tissues suggest functional roles for CYP1B1 in the bioactivation of xenobiotic procarcinogens and endogenous substrates such as estrogens. (J Histochem Cytochem 49:229-236, 2001)
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PMID:In situ hybridization and immunohistochemical analysis of cytochrome P450 1B1 expression in human normal tissues. 1115 91

This laboratory has previously reported data suggesting that aryl hydrocarbon receptor (AhR) signaling may have a net potentiating effect on the DNA damaging potential of cigarette smoke. The experiments described in this report extend these studies by testing whether the potent AhR antagonist 3'-methoxy-4'-nitroflavone (3'M4'NF) can modify the in vivo genetic toxicity of benzo[a]pyrene (B[a]P) and the complex mixture of chemicals in cigarette smoke condensate (CSC). Initial experiments were designed to determine 3'M4'NF doses which can antagonize AhR in vivo but which have little effect on constitutive cytochrome P4501A (CYP1A) activity. These experiments took three forms: (i) zoxazolamine paralysis tests, a functional assay of cytochrome P450 CYP1A activity in 3'M4'NF-treated C57Bl/6J mice; (ii) co-treatment of AHR: null allele mice with 150 mg/kg B[a]P plus a range of 3'M4'NF concentrations in order to evaluate the potential of the flavone to interact with non-AhR targets which may affect B[a]P toxicity; (iii) an evaluation of the in vivo AhR antagonist activity of 3'M4'NF using transgenic mice which carry a dioxin-responsive element-regulated lacZ reporter. Once an appropriate dose range was determined, C57Bl/6J mice were challenged with B[a]P or CSC with and without 3'M4'NF co-treatment. Chromosome damage was measured by scoring the frequency of micronuclei in peripheral blood reticulocytes. Data presented herein suggest that 3'M4'NF can protect mice from B[a]P-induced bone marrow cytotoxicity and genotoxicity. Furthermore, CSC-associated genotoxicity was abolished by the flavonoid. These data add support to our hypothesis that AhR signaling has a net potentiating effect on the genetic toxicity and, presumably, carcinogenicity of cigarette smoke.
Carcinogenesis 2001 Jan
PMID:Aryl hydrocarbon receptor signaling plays a significant role in mediating benzo[a]pyrene- and cigarette smoke condensate-induced cytogenetic damage in vivo. 1115 56

The CYP1A1 gene encodes microsomal cytochrome P4501A1 that catalyzes the metabolism of many xenobiotics, including the oxygenation of polycyclic aromatic hydrocarbons (PAH). Induction of CYP1A1 enhances the metabolism of PAHs, and therefore, represents an adaptive response to chemical exposure in mammalian cells. Mechanistic studies reveal an AhR/DRE paradigm for the induction, which involves activation of the aryl hydrocarbon receptor (AhR) by an agonist, dimerization of AhR with the Ah recceptor nuclear translocator (Arnt), followed by binding of the AhR/Arnt heterodimer to the dioxin-responsive enhancer (DRE) and transcription of the gene. The AhR mediated transcription is tightly regulated through, at least, two mechanisms: (a) the cytoplasmic AhR interacts with hsp90 and an immunophilin chaperone AIP for proper folding and receptivity, and (b) the agonist-activated, nuclear AhR is degraded through the ubiquitin-26S proteasome mediated protein turnover, such that the transcription by AhR is controlled at a physiologically adequate level. In addition to CYP1A1 induction, AhR mediates a broad range of biological responses to CYP1A1 inducers, typified by the environmental contaminant dioxin, via modulating gene expression. Thus, mechanistic studies of CYP1A1 induction have provided insights into P450 induction, PAH carcinogenesis, dioxin action, AhR function, and receptor-mediated mammalian gene expression.
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PMID:Induction of CYP1A1. The AhR/DRE paradigm: transcription, receptor regulation, and expanding biological roles. 1146 23

The compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown recently to be carcinogenic, but little is currently known about the molecular mechanism of TCDD affecting cell proliferation and carcinogenesis. In this report, we demonstrate that TCDD suppresses the expression of the checkpoint protein, Mad2. Suppression of Mad2 was also observed in aryl hydrocarbon receptor-deficient mouse embryonic fibroblasts, suggesting that TCDD suppresses Mad2 by a novel TCDD receptor signaling mechanism. In addition, HeLa cells treated with TCDD failed to arrest in mitosis after nocodazole treatment. The Mad2 protein plays a significant role in accurate chromosome segregation in mitotic cells. Our data suggest that TCDD may increase chromosomal instability through the suppression of Mad2 expression.
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PMID:Dioxin suppresses the checkpoint protein, MAD2, by an aryl hydrocarbon receptor-independent pathway. 1147 2

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous pollutant and promoter of carcinogenesis. This study investigated the interaction between TCDD and different estrogens in a cancer cell line (ID8) derived from mouse ovarian epithelium. TCDD-induced ethoxyresorufin-O-deethylase (EROD) activity and cytochrome P4501A1 (CYP1A1) expression in a dose- and time-dependent manner. Estrogen receptor (ER) alpha mRNAs were constitutively expressed, but ER beta and progesterone receptor (PR) mRNAs were not expressed. Induction of EROD by TCDD was completely inhibited by a alpha-naphthoflavone and phenanthroline, two aryl hydrocarbon receptor (AhR) antagonists. Progesterone and gonadotropins (FSH and LH) had no effect on the induction of EROD by TCDD. Congeners of 17beta-estradiol (E2) increased the induction of EROD activity by TCDD dose-dependently in the relative potency order: estrone (El)>E2> or = 4-hydroxyestradiol (4OHE2)> or = 2-hydroxyestradiol (2OHE2). In contrast, estriol (E3) decreased EROD activity induced by TCDD. E2 increased TCDD-induced CYP1A1 protein and mRNA whereas E3 decreased both the protein and mRNA. E2 did not alter luciferase activity induced by TCDD in cells transfected with a luciferase reporter containing dioxin response elements (DRE) or a CYP1A1 promoter. In contrast, E3 dose-dependently decreased the luciferase activity. A pure anti-estrogen (ICI 182780) inhibited the interaction between E2 and TCDD but did not block E3's effect on EROD activity. These results indicate that E2 may affect TCDD-induced CYP1A1 expression by a mechanism different from E3 in ID8 cells. It appears that the potentiation of E2 in the induction of CYP1A1 by TCDD occurs by a mechanism involving ER alpha since a specific ER antagonist blocked the potentiation. The inhibitory effect of E3 may be due to a rapid direct effect on EROD and a later suppression of CYP1A1 expression.
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PMID:Estradiol enhances and estriol inhibits the expression of CYP1A1 induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in a mouse ovarian cancer cell line. 1209 19

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an endocrine disrupting chemical (EDC), can cause carcinogenesis, immunosuppression, and teratogenesis, through a ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR). Despite remarkable recent advances in stem cell biology, the influence of TCDD on hematopoietic stem cells (HSCs), which possess the ability to reconstitute long-term multilineage hematopoiesis, has not been well investigated. In this study we examined the influence of TCDD on HSCs enriched for CD34(-), c-kit(+), Sca-1(+), lineage negative (CD34-KSL) cells. The number of the CD34-KSL cells was found to be increased about four-fold upon a single oral administration of TCDD (40 micro g/kg body weight). Surprisingly, we found that these TCDD-treated cells almost lost long-term reconstitution activity. This defect was not present in AhR(-/-) mice. These findings suggest that modulation of AhR/ARNT system activity may have an effect on HSC function or survival.
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PMID:TCDD treatment eliminates the long-term reconstitution activity of hematopoietic stem cells. 1260 37

Approximately 20 years after the Seveso, Italy, accident we conducted a population-based study to evaluate the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on cancer using mechanistically based biomarkers of dioxin response in humans. TCDD toxic effects are mediated by the aryl hydrocarbon receptor (AhR). We studied the AhR-dependent pathway in lymphocytes from 62 subjects randomly sampled from the highest exposed zones and 59 subjects from the surrounding non-contaminated area, frequency matched for age, gender and smoking. To our knowledge, this is the most comprehensive investigation to date designed to evaluate the key genes in the pathway, including AhR, aryl hydrocarbon receptor nuclear translocator, CYP1A1 and CYP1B1 transcripts and CYP1A1-associated 7-ethoxyresorufin O-deethylase (EROD) activity in a population heavily exposed to dioxin. Current lipid-adjusted plasma TCDD concentrations in these subjects ranged from 3.5 to 90 ng/kg (or p.p.t.) and were negatively associated with AhR mRNA in unstimulated peripheral blood mononuclear cells (P = 0.03). When mitogen-induced lymphocytes were cultured with 10 nM TCDD, all AhR-dependent genes were induced 1.2- to 13-fold. In these cells, plasma TCDD was associated with decreased EROD activity. In addition, there was a strong positive correlation between AhR and CYP1A1 expression (P = 0.001) and between AhR and CYP1B1 expression (P = 0.006). CYP1A1 expression was also strongly correlated with EROD activity (P = 0.001). The analysis of the expression of dioxin-inducible genes involved in carcinogenesis may help in determining dose-response relationships for human exposure to dioxin in vivo and in assessing the variability of human response, which may indicate the presence of subjects more susceptible to disease as a result of such exposures.
Carcinogenesis 2003 Apr
PMID:TCDD-mediated alterations in the AhR-dependent pathway in Seveso, Italy, 20 years after the accident. 1272 95

The purpose of the present studies was to use a biomarker approach to examine xenobiotic exposure of brown bullhead in Presque Isle Bay, Lake Erie (USA). In particular, the presence of compounds that act through the aryl hydrocarbon receptor (AhR) was of interest due to its central role in gene regulation and carcinogenesis of dioxins and certain polycyclic aromatic hydrocarbons (PAHs). Initial screening of Presque Isle Bay sediment samples by gene expression microarray in mouse hepatocytes revealed prototypical dioxin-response genes such as cytochrome P450 1A1 and 1B1 (CYP1A1 and CYP1B1). The presence of AhR ligands in sediment samples was confirmed and quantified using an in vitro assay, the Chemical Activated Luciferase Expression (CALUX) assay. The CALUX assay system, by using different incubation times, allows for determination of total dioxin induction equivalents (IEQ) for less persistent compounds such as PAHs as well as for stable compounds such as polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and certain polychlorinated biphenyls (PCBs). Parts of Presque Isle Bay have significant concentrations of AhR ligands in sediment ranging from 200 to 1400 parts per trillion (ppt) dioxin IEQ equivalents (dry weight). This is much higher than levels of dioxin equivalents found in similar sediment samples (approximately 10 ppt). Cascade Creek appears to be a major source of dioxin-like contaminants as IEQs in sediments taken from various regions of this tributary ranged from 1300 to 42000 ppt IEQ. In addition, the CALUX assay indicated that the majority of the IEQs (>90%) in PIB samples were in fact derived from less stable compounds. To determine if brown bullhead are exposed and respond to these high levels of AhR ligands, CYP1A cDNA was cloned from this species and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was used to examine mRNA levels. The CYP1A mRNA concentration was lower and less variable in fish taken from Presque Isle Bay than from a body of water with much lower AhR ligand concentration. Taken together, these studies show that sediment in Presque Isle Bay is highly contaminated with AhR ligands including dioxins and PAHs, but the brown bullhead are either not exposed or are non-responsive to these carcinogenic compounds.
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PMID:Evidence of aryl hydrocarbon receptor ligands in Presque Isle Bay of Lake Erie. 1284 97

Exposure to the environmental contaminant dioxin, elicits a variety of responses, which includes tumor promotion, embryotoxicity/teratogenesis, and carcinogenesis in both animals and humans. Many of the effects of dioxin are mediated by the aryl hydrocarbon receptor (AHR), a ligand-activated bHLH (basic helix-loop-helix)/PAS transcription factor. We initiated this study to determine whether dioxin's tumor-promoting activities may lie in its ability to alter proliferation, differentiation, and/or senescence using normal human epidermal keratinocytes (HEKs). Here, we report that dioxin appears to accelerate differentiation as measured by flow cytometry and by increased expression of the differentiation markers involucrin and filaggrin. In addition, dioxin appears to increase proliferation as indicated by an increase in NADH/NADPH production and changes in cell cycle. Finally, dioxin decreases SA (senescence associated) beta-galactosidase staining, an indicator of senescence, in the differentiating keratinocytes. These changes were accompanied by decreases in the expression levels of key cell cycle regulatory proteins p53, p16INK4a, and p14ARF. Our findings support the idea that dioxin may exert its tumor-promoting actions, in part, by downregulating the expression levels of key tumor suppressor proteins, which may impair the cell's ability to maintain its appropriate cellular status.
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PMID:Alteration of keratinocyte differentiation and senescence by the tumor promoter dioxin. 1455 Jul 47


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