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)

The oxidative metabolites of estrogen have been proposed to play an important role in the development of some human cancers. The two major pathways of estrogen metabolism, to the carcinogenic 4-hydroxyestradiol (4-OHE2) and to the non-carcinogenic 2-hydroxyestradiol (2-OHE2), are mediated by cytochromes P450 CYP1B1 and CYP1A1, respectively. The expression of CYP1A1 and CYP1B1 is regulated by the aromatic hydrocarbon receptor/Ah receptor nuclear translocator (AhR/ARNT) transcription factor complex. CYP1B1 expression is elevated in a wide range of human cancers but is not found in corresponding normal tissue. Thioredoxin-1 (Trx-1) is a small redox protein that is overexpressed in a number of human cancers. We report that the expression of CYP1B1 mRNA and protein is increased by Trx-1 transfection of MCF-7 human breast cancer cells and decreased by a redox inactive mutant Trx-1. The Trx-1 inhibitor PX-12 inhibits CYP1B1 gene expression. Trx-1 transfected MCF-7 cells show increased AhR/ARNT DNA binding activity that is not due to altered AhR or ARNT protein expression. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin) induced expression of CYP1B1 in MCF-7 cells is increased by Trx-1. Trx-1 does not effect the basal expression of CYP1A1, but increases CYP1A1 mRNA in response to TCDD. The redox inactive mutant Trx-1 completely blocks the induction of both CYP1B1 and CYP1A1 by TCDD. Expression of CYP1A1 but not CYP1B1 has been linked to estrogen receptor (ERalpha) status. Trx-1 transfected MCF-7 cells have decreased ERalpha expression, which may account for the lack of CYP1A1 induction by Trx-1 in the absence of ligand. The results suggest that Trx-1 is involved in the constitutive expression of CYP1B1 and is required for the induction of CYP1B1 and CYP1A1 by TCDD in human MCF-7 breast cancer cells.
Carcinogenesis 2002 Oct
PMID:The redox protein thioredoxin-1 regulates the constitutive and inducible expression of the estrogen metabolizing cytochromes P450 1B1 and 1A1 in MCF-7 human breast cancer cells. 1237 70

Susceptibility to colorectal cancer, one of the most common forms of cancer in the Western world, has been associated with several environmental and dietary risk factors. Dietary exposure to food derived heterocyclic amine carcinogens and polycyclic aromatic hydrocarbons have been proposed as specific risk factors. Many polymorphic Phase I and Phase II drug metabolizing enzymes are responsible for the metabolism and disposition of these compounds and it is therefore possible that inheritance of specific allelic variants of these enzymes may influence colorectal cancer susceptibility. In a multicenter case-control study, 490 colorectal cancer patients and 593 controls (433 matched case-control pairs) were genotyped for common polymorphisms in the cytochrome P450 (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2C9, CYP2C19 and CYP2D6), glutathione S-transferase (GSTM1, GSTP1 and GSTT1), sulfotransferase (SULT1A1 and SULT1A2), N-acetyl transferase 2 (NAT2), NAD(P)H:quinone oxidoreductase (NQO1), methylenetetrahydrofolate reductase (MTHFR), and microsomal epoxide hydrolase (EPHX1) genes. Matched case-control analysis identified alleles associated with higher colorectal cancer risk as carriage of CYP1A1*2C (OR = 2.15, 95% CI 1.36-3.39) and homozygosity for GSTM1*2/*2 (OR = 1.53, 95% CI 1.16-2.02). In contrast, inheritance of the CYP2A6*2 (OR = 0.51, 95% CI 0.28-1.06), CYP2C19*2 (OR = 0.72, 95% CI 0.52-0.98) and the EPHX1(His113) alleles were associated with reduced cancer risk. We found no association with colorectal cancer risk with NAT2 genotype or any of the other polymorphic genes associated with the metabolism and disposition of heterocyclic amine carcinogens. This data suggests that heterocyclic amines do not play an important role in the aetiology of colorectal cancer but that exposure to other carcinogens such as polycyclic aromatic hydrocarbons may be important determinants of cancer risk.
Carcinogenesis 2002 Nov
PMID:A pharmacogenetic study to investigate the role of dietary carcinogens in the etiology of colorectal cancer. 1241 32

There is significant human exposure to polycyclic aromatic hydrocarbons (PAHs), many of which are potent carcinogens in laboratory animals and are suspected human carcinogens. The PAHs are bioactivated by cytochrome P450 (CYP)1A1/1B1 enzymes to reactive intermediates that bind to DNA, a critical step in the initiation of carcinogenesis. The Ah receptor (AHR) plays a critical role in the induction of CYP1 enzymes (i.e., CYP1A1, 1A2 and 1B1) by PAHs such as benzo[a]pyrene (BP) and 3-methylcholanthrene (MC). In our investigation, we tested the hypothesis that AHR-null animals are less susceptible to PAH-induced DNA adduct formation than wild-type animals. Wild-type [AHR (+/+)] mice or mice lacking the gene for the AHR were treated with a single dose (100 micromol/kg) of BP or MC, and hepatic DNA adducts were analyzed by (32)P-postlabeling. BP induced multiple hepatic DNA adducts in wild-type as well as AHR-null animals, suggesting the existence of AHR-independent mechanisms for BP metabolic activation. On the other hand, DNA adduct formation was markedly suppressed in AHR-null animals exposed to MC, although the major MC-DNA adduct was produced in these animals. Hepatic activities and apoprotein contents of 7-ethoxyresorufin O-deethylase (EROD) (CYP1A1) and 7-methoxyresorufin O-demethylase (MROD) (CYP1A2) activities were markedly induced by BP and MC in the wild-type, but not, in AHR-null animals. CYP1B1 expression was also induced, albeit to a lesser extent by the PAH MC, but not BP, in the wild-type animals. In conclusion, these results demonstrate the existence of AHR- and CYP1A1-independent mechanisms of PAH metabolic activation in mouse liver, a phenomenon that may have important implications for PAH-mediated carcinogenesis.
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PMID:Polycyclic aromatic hydrocarbon-inducible DNA adducts: evidence by 32P-postlabeling and use of knockout mice for Ah receptor-independent mechanisms of metabolic activation in vivo. 1245 47

The xenobiotic-metabolizing P450s have been extensively studied for their ability to metabolize endogenous and exogenous chemicals. The latter include drugs and dietary and environmentally derived toxicants and carcinogens. These enzymes also metabolize endogenous steroids and fatty acids. P450s are thought to be required for efficient removal of most xenobiotics from the body and to be responsible for the hazardous effects of toxicants and carcinogens based on their ability to convert chemicals to electrophilic metabolites that can cause cellular damage and gene mutations. P450 catalytic activities have been extensively studied in vitro and in cell culture, yielding considerable information on their mechanisms of catalysis, substrate specificities, and metabolic products. Targeted gene disruption has been used to determine the roles of P450s in intact animals and their contributions to the mechanisms of toxicity and carcinogenesis. The P450s chosen for study, CYP1A1, CYP1B1, CYP1A2, and CYP2E1, are conserved in mammals and are known to metabolize most toxicants and chemical carcinogens. Mice lacking expression of these enzymes do not differ from wild-type mice, indicating that these P450s are not required for development and physiological homeostasis. However, the P450 null mice have altered responses to the toxic and carcinogenic effects of chemicals as compared with wild-type mice. These studies establish that P450s mediate the adverse effects of drugs and dietary, environmental, and industrial chemicals and serve to validate molecular epidemiology studies that seek to determine links between P450 polymorphisms and susceptibility to chemically associated diseases. More recently, P450 humanized mice have been produced.
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PMID:Study of P450 function using gene knockout and transgenic mice. 1246 54

We showed previously that CYP1B1-null mice developed 10 times less lymphomas than wild-type mice after receiving 7,12-dimethylbenz[a]anthracene (DMBA). In this study a 10-fold lower dose was applied to differentiate between toxicity induced lymphomas (200 micro g/mouse/day) and tumor initiation (20 micro g/day). DMBA adducts to DNA of organs of mice, or to DNA of V79 cells expressing single mice or human cytochrome P450 isoenzymes were also measured. Mice were dosed three cycles of 5 days/week with DMBA in corn oil orally. Histopathology was determined at intermittent death or 1 year after dosing. DMBA-DNA adducts were assayed by (32)P-postlabeling. At 20 micro g/day, wild-type mice developed ovary (71%, stromal cells derived), skin (36%), uterus (64%) and lung (14%) hyperplasias. At this dose the CYP1B1-null mice developed no lymphomas, 25% ovary (epithelial cells derived), 8% skin, 58% uterus and 33% lung tumors. Oil control mice (n = 35) developed only eight, mostly different, hyperplasias. Wild-type mice had more DMBA-DNA adducts than the CYP1B1-null mice. The differences were highest in thymus, spleen, ovaries and testes (5-7-fold). Additionally, one specific DMBA-DNA adduct was reduced in CYP1B1-null mice. V79-cells expressed mouse CYP1B1 was 35 times more active than mouse CYP1A1 in forming DMBA-DNA adducts. Human CYP1B1 was 2.5 times less active than mouse CYP1B1 but 2.3-fold more active than human CYP1A1. CYP1B1 is the dominant enzyme in metabolizing DMBA to carcinogenic metabolites at high and low doses in mice, leading to an increased tumor rate of especially the ovaries at low doses of DMBA. Wild-type mice had more DMBA-DNA adducts than CYP1B1-null mice. Additionally, a specific adduct was less present in the CYP1B1-null mice. Human CYP1B1 was less active than mouse CYP1B1, but more active than human CYP1A1 in forming DMBA-DNA adducts. Thus, we expect CYP1B1 to be an important DMBA activating enzyme in humans also.
Carcinogenesis 2003 Feb
PMID:CYP1B1 determines susceptibility to low doses of 7,12-dimethylbenz[a]anthracene-induced ovarian cancers in mice: correlation of CYP1B1-mediated DNA adducts with carcinogenicity. 1258 84

Tissue-specific induction of mRNA of cytochrome P450 (P450 or CYP) 1A1 and 1B1 by polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) was investigated in wild and arylhydrocarbon receptor (AhR)-deficient C57BL/6J mice. Ratios of mRNA expression of CYP1A1 or CYP1B1 over beta-actin were determined and used to compare levels of expression and induction of these P450s by PAHs and PCBs in various organs. CYP1A1 mRNA was detected in control mice at very low levels in liver, lung, heart, kidney, intestine, thymus, testis, uterus, ovary, and brain and was highly induced in these organs by benzo[a]pyrene and 3,4,3',4'-tetrachlorobiphenyl in AhR(+/+) mice. In AhR(+/+) and AhR(-/-) mice, CYP1B1 mRNA was found to be constitutively expressed at significant levels in heart (the ratio of mRNAs of CYP1B1 to beta-actin was approximately 0.6), kidney ( approximately 0.8), intestine ( approximately 0.3), testis ( approximately 0.9), thymus ( approximately 0.4), uterus ( approximately 0.3), ovary ( approximately 1.4), and brain ( approximately 0.4), whereas it was low in liver and lung (the mRNA ratio to beta-actin was <0.2 in these cases). CYP1B1 in the latter two organs was highly induced by PAHs and 3,4,3',4'-tetrachlorobiphenyl in AhR(+/+) mice. The induction of CYP1B1 by PAHs and PCBs was more extensive in organs in which the constitutive expression of CYP1B1 was low. For example, CYP1B1 was induced 9-fold and 10-fold by benzo[a]pyrene and 3,4,3',4'-tetrachlorobiphenyl in livers of male and female mice, respectively, whereas in testis and ovary, the fold induction of CYP1B1 by two inducers was only 1.1 and 1.4, respectively. Liver microsomal xenobiotic oxidation activities were induced by these PAHs and PCBs in male and female AhR(+/+) mice. These results suggest that CYP1A1 and CYP1B1 are differentially regulated in their expression in extrahepatic organs of mice and could be induced by PAHs and PCBs with different extents of induction depending on the inducers used and the organs examined in AhR(+/+) mice. The findings of significant levels of constitutive expression of CYP1B1 in AhR(-/-) mice as well as AhR(+/+) mice in several organs including heart, kidney, thymus, testis, ovary, and brain in AhR(-/-) mice as well as AhR(+/+) mice are of importance in understanding the basis of toxicity and carcinogenesis by chemicals that are metabolized by CYP1B1.
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PMID:Tissue-specific induction of cytochromes P450 1A1 and 1B1 by polycyclic aromatic hydrocarbons and polychlorinated biphenyls in engineered C57BL/6J mice of arylhydrocarbon receptor gene. 1262 79

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

Metabolic activation of estradiol has been shown to be a key factor in endometrial carcinogenesis. 4-hydroxy estrogens (CYP1B1 metabolites) received particular attention because of their causative role in malignant transformation of various organs including endometrium. CYP1B1 displays the highest level of expression in endometrium. 4-hydroxy estrogens can bind to DNA via their quinone metabolites and cause oxidative damage in endometrial cancer. Moreover, the 4-hydroxy estrogens bind to the estrogen receptor and have estrogenic effects on target tissues. Six polymorphisms of the CYP1B1 gene have been described of which four result in amino acid substitutions; 1-13C-->T, codon 48C-->G, codon 119G-->T, codon 432C-->G, codon 449T-->C and codon 453A-->G. The polymorphisms on exons 2 and 3 have significant effects on the catalytic function of CYP1B1. Polymorphisms on specific regions of CYP1B1 gene result in hyperactivation of the protein and can lead to a higher susceptibility in the incidence of various cancers. Thus, inherited alterations in CYP1B1 hydroxylation activity may be associated with significant changes in estrogen metabolism and, thereby, may possibly explain inter-individual differences in endometrial cancer risk associated with estrogen-mediated carcinogenesis.
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PMID:CYP1B1 gene in endometrial cancer. 1277 Jul 47

Urinary 1-hydroxypyrene (1-OHP) has been used as a biomarker for assessing the level of exposure to environmental carcinogenic polycyclic aromatic hydrocarbons (PAHs). In order to perform the appropriate biological monitoring for examining the level of exposure to PAHs, this study investigated whether or not genetic polymorphisms of the metabolic enzymes, which might be involved in the metabolism of pyrene, affected the urinary 1-OHP levels in a population of 661 Koreans (male, 63%; female, 37%; mean age, 36.5 +/- 11.1 years) who were not occupationally exposed to PAHs. Urinary 1-OHP was detected in 76% of the subjects (range 0.001-3.8 micro g/l). Among the physical and lifestyle factors, cigarette-smoking was found to be associated with the urinary 1-OHP levels (P < 0.05). After adjusting for these factors, we found that the GSTT1 genotypes affected the urinary 1-OHP levels, i.e. the GSTT1 present subjects had approximately 1.5 times the urinary 1-OHP level than the GSTT1 null subjects (P < 0.05). In the case of the subjects who were also GSTM1 null, this trend became stronger, i.e. the GSTT1 present subjects had approximately 2 times the urinary 1-OHP level (P < 0.01). However, the genetic polymorphism of the other metabolic enzymes, cytochrome P-450 (CYP)1A1, CYP1B1 and GSTM1 alone, did not affect the urinary 1-OHP level. Therefore, this study suggests that the GSTT1 genetic polymorphism has the potential to affect the biological monitoring of PAHs with urinary 1-OHP, and might act as a genetic factor in PAH-related toxicity.
Carcinogenesis 2003 Jun
PMID:Genetic effects on urinary 1-hydroxypyrene levels in a Korean population. 1280 51

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


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