UMLS:C0596263 - FACTA Search

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Query: UMLS:C0596263 (carcinogenesis)
64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although benzo[g,h,i]perylene (BghiP) has been found to promote the carcinogenesis of benzo[a]pyrene (BaP) in animal models, not much is known about this cocarcinogenic mechanism. In this study, human hepatoma HepG2 cells cotreated with BaP and BghiP were used as a model to investigate the cocarcinogenic mechanism of BghiP in BaP-induced carcinogenesis. DNA adduct formation is thought to initiate carcinogenesis, so the effect of BghiP on BaP-DNA adduct formation was evaluated using a (32)P-postlabeling assay. The BaP-DNA adduct levels increased following the addition of BghiP, in a dose-dependent manner. However, no adducts were formed with BghiP alone. Our previous report showed that cytochrome P450 1A1 (CYP1A1) is responsible for the metabolic activation of BaP and the formation of B[a]P adduct in HepG2 cells. Western blot and Northern blot analyses were used to evaluate whether BaP-induced CYP1A1 protein and mRNA levels increased following the addition of BghiP. Our data showed that BghiP enhanced BaP-induced CYP1A1 protein and its mRNA levels. To understand whether BghiP enhances BaP-induced CYP1A1 gene expression through the aryl hydrocarbon receptor (AhR) signaling pathway, a gel retardation assay was performed to elucidate the synergistic mechanism of BghiP in BaP-induced CYP1A1 gene expression. The results showed that BghiP causes an increase in the nuclear accumulation of AhR in cells and/or activation of AhR to a DNA-binding form. There was a concordant increase in the transcription activation of CYP1A1 gene and the induction of AhR signal pathway. Our findings demonstrated that BghiP enhances BaP-induced CYP1A1 transcription by AhR activation and suggested that the induction mechanism of CYP1A1 contributes to the cocarcinogenic potential of BghiP in BaP-induced carcinogenesis.
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PMID:Benzo[g,h,i]perylene synergistically transactivates benzo[a]pyrene-induced CYP1A1 gene expression by aryl hydrocarbon receptor pathway. 1114 57

Cytochrome P450 1A1 (CYP1A1) plays a key role in the metabolism of carcinogens, such as benzo[a]pyrene (B[a]P) and metabolites to ultimate carcinogens. Three human allelic variants, namely wild-type (CYP1A1.1), CYP1A1.2 (I462V) and CYP1A1.4 (T461N), were coexpressed by coinfection of baculovirus-infected insect cells with human NADPH-P450 reductase. These recombinant enzymes (in microsomal membranes) were used to analyze whether CYP1A1 polymorphisms affect catalytic activities towards B[a]P and B[a]P-7,8-dihydrodiol. The complete spectrum of phase I metabolites, including the tetrahydrotetrols resulting from hydrolysis of the ultimate carcinogen, B[a]P-7,8-dihydrodiol-9,10-epoxide, was examined by HPLC. Wild-type enzyme showed the highest total metabolism of B[a]P, CYP1A1.2 was approximately 50%, and CYP1A1.4 approximately 70%. Km values for all metabolites with CYP1A1.2 were generally significantly lower than with wild-type enzyme (e.g. B[a]P-7,8-diol formation: 13.8 microM for wild-type, 3.5 microM for CYP1A1.2 and 7.7 microM for CYP1A1.4). Addition of epoxide hydrolase markedly increases the relative diol-to-phenol activities by all three variants. However, CYP1A1.4 exhibits the greatest efficiency to produce diol species. Each variant produced the diol epoxides from B[a]P-7,8-dihydrodiol. CYP1A1.1 exhibited with 10.4 pmol/min/pmol CYP1A1 the greatest total rate for 7,8-diol metabolites followed by CYP1A1.2 (7.2 pmol/min/pmol CYP1A1) and CYP1A1.4 (5.5 pmol/min/pmol CYP1A1). All enzyme variants produced about three times more diol epoxide 2-derived metabolites than diol epoxide 1-derived ones, whereby both rare allelic variants exhibited statistically significantly increased formation of diol epoxide 2. This study showed that the three CYP1A1 variants had different enzyme kinetics properties to produce both the diol metabolites from B[a]P and the ultimate mutagenic species diol epoxide 2 from B[a]P-7,8-dihydrodiol, which must be considered in the evaluation of individual susceptibility to cancer.
Carcinogenesis 2001 Mar
PMID:Differential metabolism of benzo[a]pyrene and benzo[a]pyrene-7,8-dihydrodiol by human CYP1A1 variants. 1123 86

The mechanism of cytotoxicity induced by the DNA-damaging carcinogen 3-amino-1,4-dimethyl-5H-pyrido[4,3-b] indole (Trp-P-1) was investigated in primary cultured rat hepatocytes. Cytotoxicity was caused by intact Trp-P-1 and not by metabolically activated derivatives prepared using a recombinant yeast strain AH22/pAMR2 expressing rat cytochrome P450 1A1, and not by metabolically activated derivatives. We also found internucleosomal DNA fragmentation 6 h after treatment with 30 microM Trp-P-1, indicating that the cytotoxicity was due to the induction of apoptosis. After treatment with Trp-P-1, c-Myc protein level increased in a time-dependent manner and p53 protein also increased transiently with a subsequent increase in Bax protein level. This apoptotic pathway required the activation of caspase-9 as an initiator after leakage of cytochrome c into the cytosol from mitochondria and the activation of caspase-3 and -7 as executioners, but not caspase-1, -6 or -8 as measured using the corresponding peptide inhibitors and substrates or western blotting. The activated caspases in turn cleaved poly(ADP-ribose) polymerase as an intracellular substrate. Furthermore, we detected NUC18-like endonuclease activity during apoptosis induced by Trp-P-1. These findings suggest that this apoptosis may have a role against heterocyclic amine-type carcinogens in normal cells.
Carcinogenesis 2001 May
PMID:DNA-damaging carcinogen 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) induces apoptosis via caspase-9 in primary cultured rat hepatocytes. 1132 86

This study was undertaken to determine the effects of occupation, lifestyle and the genetic polymorphisms of cytochrome P450 1A1 (CYP1A1), cytochrome P450 2E1 (CYP2E1) and glutathione S-transferases micro1 (GSTM1) and 1 (GSTT1) on the concentrations of urinary 1-hydroxypyrene (1-OHP) and 2-naphthol among Korean coke oven workers and university students. The study subjects included 90 coke oven workers and 128 university students. A questionnaire was used to obtain detailed data about the work area, smoking habits and food intake of subjects. Associations between urinary polycyclic aromatic hydrocarbon (PAH) concentrations and occupation, smoking status, total airborne PAH level and genetic polymorphisms were tested. Urinary 1-OHP and 2-naphthol concentrations were higher in coke oven workers than in students and correlated significantly with work area. Urinary 2-naphthol concentrations increased with an increase in the level of cigarette smoking in students. Total airborne PAH level correlated with urinary 1-OHP concentration in coke oven workers. Urinary 1-OHP and 2-naphthol concentrations were higher in coke oven workers with the c1/c2 or c2/c2 genotype of CYP2E1 than in those with the c1/c1 genotype. Urinary 2-naphthol concentrations were higher in GSTM1-null workers than in GSTM1-positive workers. In multiple regression analysis CYP2E1 was a significant factor determining urinary 1-OHP concentrations in coke oven workers. CYP2E1 and GSTM1 were significant determinants for urinary 2-naphthol concentrations in coke oven workers and GSTM1 and smoking were prognosticators among university students. Urinary 1-OHP is a better indicator of occupational exposure to PAH in coke oven workers than 2-naphthol, whereas urinary 2-naphthol may be more sensitive for non-occupational inhalation exposure to PAH. In occupationally exposed populations CYP2E1 and GSTM1 appear to play an important role in the metabolism of pyrene and naphthalene. In individuals not occupationally exposed to PAHs GSTM1 and smoking seem to influence the urinary concentration of 2-naphthol.
Carcinogenesis 2001 May
PMID:Effects of occupation, lifestyle and genetic polymorphisms of CYP1A1, CYP2E1, GSTM1 and GSTT1 on urinary 1-hydroxypyrene and 2-naphthol concentrations. 1132 99

Several selenocysteine Se-conjugates (SeCys-conjugates) prevent against chemically induced carcinogenesis. Bioactivation to selenols (RSeH) by beta-lyases is thought to be critical, but the mechanism of tumor suppression remains unclear. Induction of phase II biotransformation enzymes is a possible mechanism of chemoprevention. In this study, we evaluated the isoform-selective induction of glutathione-S-transferase (GST) at the mRNA level using a quantitative reverse transcriptase polymerase chain reaction assay. In cultured primary rat hepatocytes and H35 Reuber rat hepatoma cells, SeCys-conjugates time-dependently increased mRNA levels of GST Alpha isoforms and GST Pi, but not of GST Mu isoforms. Se-allyl-L-selenocysteine, the most potent chemopreventive SeCys-conjugate so far known, was also the most active GST inducer. After exposure for 24hr, it elevated GSTA2, GSTA3, GSTA5, and GSTP mRNA levels in primary hepatocytes 3.2+/-0.4-, 1.9+/-0.1-, 4.3+/-0.3-, and 2.9+/-0.3-fold, respectively. Se-allyl-D-selenocysteine was significantly less active, suggesting that stereoselective conversion of SeCys-conjugates to selenols is involved in GST induction. In H35 Reuber hepatoma cells, where conversion of SeCys-conjugates to selenols was 2-6-fold lower than in primary hepatocytes, GST induction was also much lower than in primary hepatocytes. SeCys-conjugates did not induce cytochrome P450 1A1, 2B1/2, or 3A1. This indicates that SeCys-conjugates are monofunctional inducers of phase II biotransformation enzymes. The present results suggest that induction of GST expression contributes to the chemopreventive activity of SeCys-conjugates.
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PMID:Induction of glutathione-S-transferase mRNA levels by chemopreventive selenocysteine Se-conjugates. 1203 68

Human cytochrome P450 1A1, which is present in lungs, plays an important role in the metabolic activation of chemical carcinogens, and in particular, is thought to be linked to lung cancer. The mechanism of carcinogenesis is related to the enzyme's ability to oxidize highly toxic compounds, such as polycyclic aromatic hydrocarbons (PAHs), to their carcinogenic derivatives. In order to better understand P450 1A1 function, a homology model of this enzyme has been constructed. The model has been based on the structure of P450 2C5, the first mammalian P450 to be crystallized. The coordinates of the model have been calculated using a consensus strategy, and the resulting structure has been evaluated with the ProStat and Profiles-3D programs. P450 1A1 substrates, such as benzo[a]pyrene, ethoxyresorufin and methoxyresorufin, were then docked into the active site of the model, and key amino acid residues able to interact with the substrate, have been identified. The analysis of enzyme-substrate interactions indicated that hydrophobic interactions are mainly responsible for binding of these substrates in the active site. Moreover, the non-bond enzyme-substrate interaction energy for ethoxyresorufin was lower than that for methoxyresorufin, which is consistent with higher activity of 1A1 towards the former substrate. Key residue Val-382 may play an important role in these interactions. Additionally, we performed binding free energy calculations for the three substrates. The obtained values were similar to those observed experimentally, which suggests that this approach might be useful for prediction of binding constants.
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PMID:Molecular modeling of cytochrome P450 1A1: enzyme-substrate interactions and substrate binding affinities. 1235 67

Polymorphisms for genes encoding the metabolic enzymes cytochrome P450 1A1 (CYP1A1) and glutathione S-transferase M1 (GSTM1) might contribute to the variability in individual susceptibility to lung cancer. The role of CYP1A1 and GSTM1 in lung carcinogenesis might be more important at low levels of exposure to carcinogens. Non-smokers represent a population at low exposure, however, they are often overlooked because of the small number of cases. We therefore conducted a pooled analysis of 14 case-control studies on lung cancer in Caucasian non-smokers with comparable information on genetic polymorphisms included in the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens. We pooled the raw data from a total of 302 cases and 1631 controls with random effects models. We also evaluated the possibility of inclusion bias and conducted influence analyses. The odds ratio (OR) of lung cancer for the variant CYP1A1 Ile(462)Val polymorphism (Ile/Val, Val/Val) was 2.99 [95% confidence interval (95%CI) 1.51-5.91]; this effect was stronger on lung adenocarcinoma (OR 4.85, 95%CI 2.03-11.6). After excluding outlying or imprecise studies, we did not observe a significant effect of the CYP1A1 MspI (T(3801)C) polymorphism or GSTM1 null genotype (OR 1.20, 95%CI 0.89-1.63). Furthermore, our analyses suggested a combined effect of the CYP1A1 Ile(462)Val polymorphism and GSTM1 null genotype. The OR for the combination of the CYP1A1 Ile(462)Val variant and GSTM1 null genotype was 4.67 (95%CI 2.00-10.9) compared with the concurrent presence of the CYP1A1 wild-type and GSTM1 non-null genotype. We did not observe a modification of the effect of the GSTM1 null genotype according to exposure to environmental tobacco smoke and urban/rural residence. Our study therefore suggests that the CYP1A1 Ile(462)Val variant allele might play a role in lung carcinogenesis among non-smokers, possibly in combination with the GSTM1 null genotype.
Carcinogenesis 2003 May
PMID:CYP1A1 and GSTM1 genetic polymorphisms and lung cancer risk in Caucasian non-smokers: a pooled analysis. 1277 Oct 31

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

Resveratrol (3,5,4'-trihydroxystilbene), a naturally occurring phytoalexin present in grapes and other foods, has been reported to possess chemopreventive effects as revealed by its striking inhibition of diverse cellular events associated with tumor initiation, promotion and progression. In our present study, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), when treated with the cultured human mammary epithelial (MCF-10A) cells, induced the expression of cytochrome P450 1A1 (CYP1A1) and 1B1 (CYP1B1) that are responsible for the oxidation of 17beta-estradiol to produce catechol estrogens. Resveratrol strongly inhibited the TCDD-induced aryl hydrocarbon receptor (AhR) DNA binding activity, the expression of CYP1A1 and CYP1B1 and their catalytic activities in MCF-10A cells. It also reduced the formation of 2-hydroxyestradiol and 4-hydroxyestradiol from 17beta-estradiol by recombinant human CYP1A1 and CYP1B1, respectively. Furthermore, resveratrol significantly attenuated the intracellular reactive oxygen species (ROS) formation and oxidative DNA damage as well as the cytotoxicity induced by the catechol estrogens. Our data suggest that CYP1A1- and CYP1B1-catalyzed catechol estrogen formation might play a key role in TCDD-induced oxidative damage, and resveratrol can act as a potential chemopreventive against dioxin-induced human mammary carcinogenesis by blocking the metabolic formation of the catechol estrogens and scavenging the ROS generated during their redox cycling.
Carcinogenesis 2004 Oct
PMID:Resveratrol inhibits TCDD-induced expression of CYP1A1 and CYP1B1 and catechol estrogen-mediated oxidative DNA damage in cultured human mammary epithelial cells. 1514 86

Glycine N-methyltransferase (GNMT) affects genetic stability by (a) regulating the ratio of S-adenosylmethionine to S-adenosylhomocystine and (b) binding to folate. Based on the identification of GNMT as a 4 S polyaromatic hydrocarbon-binding protein, we used liver cancer cell lines that expressed GNMT either transiently or stably in cDNA transfections to analyze the role of GNMT in the benzo(a)pyrene (BaP) detoxification pathway. Results from an indirect immunofluorescent antibody assay showed that GNMT was expressed in cell cytoplasm before BaP treatment and translocated to cell nuclei after BaP treatment. Compared with cells transfected with the vector plasmid, the number of BaP-7,8-diol 9,10-epoxide-DNA adducts that formed in GNMT-expressing cells was significantly reduced. Furthermore, the dose-dependent inhibition of BaP-7,8-diol 9,10-epoxide-DNA adduct formation by GNMT was observed in HepG2 cells infected with different multiplicities of infection of recombinant adenoviruses carrying GNMT cDNA. According to an aryl hydrocarbon hydroxylase enzyme activity assay, GNMT inhibited BaP-induced cytochrome P450 1A1 enzyme activity. Automated BaP docking using a Lamarckian genetic algorithm with GNMT X-ray crystallography revealed a BaP preference for the S-adenosylmethionine-binding domain of the dimeric form of GNMT, a novel finding of a cellular defense against potentially damaging exposures. In addition to GNMT, results from docking experiments showed that BaP binds readily with other DNA methyltransferases, including HhaI, HaeIII, PvuII methyltransferases and human DNA methyltransferase 2. We therefore hypothesized that BaP-DNA methyltransferase and BaP-GNMT interactions may contribute to carcinogenesis.
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PMID:Glycine N-methyltransferase tumor susceptibility gene in the benzo(a)pyrene-detoxification pathway. 1515 Jan 20

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