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 relationships between smoking and the expression of glutathione S-transferase (GST*) isozymes GSTM1-1, GSTM3-3, GSTP1-1 and GSTA1-1/2-2 (GSTA1/2), or between smoking and activities of epoxide hydrolase (EH) and aryl hydrocarbon hydroxylase (AHH) were investigated in lung samples from 27 patients with lung cancer and 11 control patients by immunoblot analysis and enzyme assays. Determination of genotypes in blood leucocyte DNA showed that possession of the mu-class GSTM1 gene was closely related to the expression of GSTM1-1 and GSTM3-3 enzymes in lung cytosol: patients with the GSTM1 null genotype had no detectable GSTM1 protein and less GSTM3 protein than patients with the GSTM1 gene (P < 0.001). Absence of the GSTM1 gene did not affect the content of phi-class GSTP1-1 or alpha-class GSTA1/2. GST activity towards 1-chloro-2,4-dinitrobenzene was lower (P < 0.01) in patients lacking the GSTM1 gene than in those expressing GSTM1; in general, patients with a low GSTM3-3, GSTP1-1 or GSTA1/2 content also had significantly less overall GST activity. The pulmonary content of GSTP1-1 was greater in cancer than in non-cancer patients (P < 0.05). Smoking did not influence the levels of GST isozymes or the EH activity. In contrast, the AHH activity was significantly (P < 0.01) increased by smoking. Neither AHH nor EH showed a correlation with GSTM1 polymorphism. Our data support the idea that in smokers who lack the GSTM1 gene, activation of carcinogens in tobacco smoke (e.g. benzo[alpha]pyrene) is increased, while the efficacy of detoxification is limited both qualitatively (absence of GSTM1-1 enzyme and low expression of GSTM3-3 enzyme) and quantitatively (low overall GST activity). This imbalance in the metabolism of carcinogens may explain the increased susceptibility to lung cancer reported in smokers with the GSTM1 null genotype.
Carcinogenesis 1995 Apr
PMID:Expression and polymorphism of glutathione S-transferase in human lungs: risk factors in smoking-related lung cancer. 772 47

The carcinogenic potency of many mutagens is increased in conditions of tissue regeneration. This involves fundamental changes of cellular division and differentiation, in intestinal epithelium. However, effects on epithelial capacity for carcinogen metabolism and susceptibility to genotoxic injury are unknown. Using a novel rat model, this study assessed expression of cytochrome P450 mono-oxygenases (Cyps), glutathione S-transferases (GSTs) and uridine diphosphoglucuronosyl transferase (UGT) in intestinal epithelium during sequential stages of regeneration. Enzyme induction and DNA adduct formation were also assessed after benzo[a]pyrene (BaP) exposure. Control assays were carried out in normal intestinal epithelium. Fewer phase I and II xenobiotic metabolizing enzymes were expressed in regenerating intestinal epithelium than in normal control intestinal epithelium (GSTA3, UGT in regeneration vs Cyp2B, GSTA1/2, GSTA4, GSTP1, UGT in control). Benzo[a]pyrene induced GSTA3 and UGT in regeneration vs Cyp1A, Cyp2B, GSTA1/2, GSTA3, GSTA4, GSTP1 and UGT in control normal intestinal epithelium. Benzo[a]pyrene induced low levels of GSTA3 in early regenerating intestinal epithelium but induction increased by >2-fold at late stage regeneration. Higher levels of benzo[a]pyrene 7,8-diol-9,10-epoxide (BPDE) DNA adducts were formed at early stages of regeneration, than at later stages. Intestinal epithelium displayed reduced metabolic competence and differential susceptibility to genotoxic injury from BaP, during regeneration.
Carcinogenesis 1997 Nov
PMID:Metabolic competence and susceptibility of intestinal epithelium to genotoxic injury during regeneration. 939 18

Glucoraphanin in Brassica vegetables breaks down to either sulforaphane or sulforaphane nitrile depending on the conditions, and sulforaphane can be further conjugated with glutathione. Using a high-throughput microtitre plate assay and TaqMan real time quantitative RT-PCR to measure mRNA, we show that sulforaphane and its glutathione conjugate, but not the nitrile, increased significantly (P < 0.05) both UGT1A1 and GSTA1 mRNA levels in HepG2 and HT29 cells. These changes were accompanied by an increase in UGT1A1 protein, as assessed by immunoblotting, and a 2-8-fold increase in bilirubin glucuronidation. When treated together, the nitrile derivative did not affect sulforaphane induction. The induction of UGT1A1 and GSTA1 mRNA by sulforaphane was time and concentration dependent. The results show a functional induction of glucuronidation by sulforaphane but not sulforaphane nitrile, and show that the pathway of metabolism of glucosinolates in Brassica vegetables is important in determining the resulting biological and anticarcinogenic activities.
Carcinogenesis 2002 Aug
PMID:Sulforaphane and its glutathione conjugate but not sulforaphane nitrile induce UDP-glucuronosyl transferase (UGT1A1) and glutathione transferase (GSTA1) in cultured cells. 1215 60

The glutathione S-transferases (GSTs) are a multigene family of enzymes largely involved in the detoxification of chemicals. In animals, enhanced expression is mediated by products of gut fermentation. Of these, butyrate induces GSTP1 protein expression and GST activity in the human colon tumor cell line HT29. The aim of the following investigations was to further elucidate butyrate-modulated induction of additional colonic GSTs in HT29 and to determine baseline expression in non-transformed cells, isolated from human colorectal tissue. We measured five GST protein subunits (GSTA1/2-composed of GST A1-1, A1-2 and A2-2-GSTM1, GSTM2, GSTP1, GSTT1) by western blot, GST activity using 1-chloro-2,4-dinitrobenzene as substrate and GSTM2 mRNA expression with RT-PCR. GSTP1, followed by GSTT1, were major subunits in all colon cells. Cells isolated from colon tissue were identified to be colonocytes and colon fibroblasts, both of which also expressed substantial levels of GSTM1 and GSTM2. The inter-individual variation of GST subunits in coloncytes of 15 individuals was marked, with total GST protein per 106 cells differing by more than a factor of four. In HT29, butyrate significantly enhanced GSTA1/2 (3.5-fold), GSTM2 (not detectable in controls), GSTP1 (1.5-fold) and GST activity (1.4-fold), but not GSTM1 or GSTT1. GSTM2 mRNA expression was significantly induced after 24 ( approximately 14-fold) and 72 h treatment ( approximately 8-fold). In colon fibroblasts, butyrate (4 mM, 72 h) also induced GSTM2 protein (1.7-fold) and GST activity (1.4-fold). Colonocytes were too short lived to be used for inducibility studies. In conclusion, GSTs are expressed with high inter-individual variability in human colonocytes. This points to large differences in cellular susceptibility to xenobiotics. However, butyrate, an important luminal component produced from fermentation of dietary fibers, is an efficient inducer of GSTs and especially of GSTM2. This indicates that butyrate may act chemoprotectively by increasing detoxification capabilities in the colon mucosa.
Carcinogenesis 2003 Oct
PMID:Expression of glutathione S-transferases (GSTs) in human colon cells and inducibility of GSTM2 by butyrate. 1289 3

Somatic inactivation of the glutathione S-transferase-pi gene (GSTP1) via CpG island hypermethylation occurs early during prostate carcinogenesis, present in approximately 70% of high-grade prostatic intraepithelial neoplasia (high-grade PIN) lesions and more than 90% of adenocarcinomas. Recently, there has been a resurgence of the concept that foci of prostatic atrophy (referred to as proliferative inflammatory atrophy or PIA) may be precursor lesions for the development of prostate cancer and/or high-grade PIN. Many of the cells within PIA lesions contain elevated levels of GSTP1, glutathione S-transferase-alpha (GSTA1), and cyclooxygenase-II proteins, suggesting a stress response. Because not all PIA cells are positive for GSTP1 protein, we hypothesized that some of the cells within these regions acquire GSTP1 CpG island hypermethylation, increasing the chance of progression to high-grade PIN and/or adenocarcinoma. Separate regions (n =199) from 27 formalin-fixed paraffin-embedded prostates were microdissected by laser-capture microdissection (Arcturus PixCell II). These regions included normal epithelium (n = 48), hyperplasticepithelium from benign prostatic hyperplasia nodules (n = 22), PIA (n = 64), high-grade PIN (n = 32), and adenocarcinoma (n = 33). Genomic DNA was isolated and assessed for GSTP1 CpG island hypermethylation by methylation-specific polymerase chain reaction. GSTP1 CpG island hypermethylation was not detected in normal epithelium (0 of 48) or in hyperplastic epithelium (0 of 22), but was found in 4 of 64 (6.3%) PIA lesions. The difference in the frequency of GSTP1 CpG island hypermethylation between normal or hyperplastic epithelium and PIA was statistically significant (P = 0.049). Similar to studies using nonmicrodissected cases, hypermethylation was found in 22 of 32 (68.8%) high-grade PIN lesions and in 30 of 33 (90.9%) adenocarcinoma lesions. Unlike normal or hyperplastic epithelium, GSTP1 CpG island hypermethylation can be detected in some PIA lesions. These data support the hypothesis that atrophic epithelium in a subset of PIA lesions may lead to high-grade PIN and/or adenocarcinoma. Because these atrophic lesions are so prevalent and extensive, even though only a small subset contains this somatic DNA alteration, the clinical impact may be substantial.
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PMID:Hypermethylation of the human glutathione S-transferase-pi gene (GSTP1) CpG island is present in a subset of proliferative inflammatory atrophy lesions but not in normal or hyperplastic epithelium of the prostate: a detailed study using laser-capture microdissection. 1293 33

2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant heterocyclic amine derived from food, possibly involved in human carcinogenesis. We evaluated the formation of PhIP-DNA adducts in lymphocytes from 76 incident colorectal cancer patients likely to be exposed to dietary PhIP. To address the role of the metabolic polymorphisms relevant to PhIP-DNA adduct formation, the patients were genotyped for common polymorphisms in the N-acetyltransferase (NAT1 and NAT2), sulfotransferase (SULT1A1) and glutathione S-transferase (GSTM1 and GSTA1) genes. PhIP released from adducted DNA after hydrolysis was quantitated by liquid chromatography-tandem mass spectrometry. Overall, adducts were 3.24 +/- 3.58/10(8) nucleotides (mean +/- SD); they were not related to sex, smoking habits or age, though levels were not significantly higher in smokers, young subjects and high meat consumers. High vegetable intake significantly reduced PhIP-DNA adducts (Mann-Whitney U, p = 0.044). Individuals with the GSTM1 null genotype showed colon cancer onset at earlier age (58.8 +/- 1.8 vs. 63.5 +/- 1.6 years; Mann-Whitney U, p = 0.047). None of the genetic polymorphisms studied significantly affected PhIP-DNA adducts. However, individuals carrying 2 mutated GSTA1 alleles and younger than the median age had higher adduct levels than homozygous wild-type and heterozygous ones (Kruskal-Wallis p = 0.0008). In conclusion, these preliminary data indicate that PhIP-DNA adducts are formed in people likely to be exposed to this carcinogen through the diet, suggesting this biomarker may be useful to detect human exposure and DNA damage. Overall, the genetic polymorphisms considered had limited effect on PhIP-DNA levels, but young people with lower detoxification capacity may form a subgroup particularly susceptible to dietary carcinogen.
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PMID:Genetic polymorphisms and modulation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-DNA adducts in human lymphocytes. 1460 Oct 45

The isothiocyanate, sulforaphane and the flavonoid, apigenin modulate gene expression including phase II detoxifying enzymes, such as glutathione S-transferases (GST) and UDP-glucuronosyltransferases (UGT). Using undifferentiated CaCo-2 cells, we have examined the interactions between sulforaphane and apigenin in the regulation of UGT and GST expression. We show that apigenin induces UGT1A1 transcription (4-fold) but not GSTA1, and that sulforaphane induces both UGT1A1 (3.7-fold) and GSTA1 (2.8-fold) transcription in both dose- and time-dependent manners. The combination of sulforaphane and apigenin resulted in a synergistic induction of UGT1A1 mRNA up to 12-fold, although this interaction was not seen for GSTA1. Nuclear factor kappa B (NF-kappaB) mRNA was induced by apigenin and sulforaphane (2.5- and 2-fold, respectively). NF-kappaB translocation inhibitor SN50 and phosphatidylinositol 3-kinase (PI3) inhibitor LY294002 decreased the induction of GSTA1 by sulforaphane almost to baseline level. However, the MEK inhibitor PD98059 enhanced significantly the induction of GSTA1 by sulforaphane. This suggests that NF-kappaB and PI3-kinase signaling pathways play a role in GSTA1 gene expression. Conversely, the induction of UGT1A1 transcription by sulforaphane was totally abolished by PD98059, although PD98059 slightly enhanced (20%) the induction of UGT1A1 by apigenin implying that the induction of UGT1A1 by sulforaphane is mediated by MAPK/extracellular signal-regulated kinase kinase, whereas UGT1A1 induction by apigenin may be associated with NF-kappaB translocation since the NF-kappaB translocation inhibitor, SN50 enhanced the induction of UGT by apigenin. The results show that UGT1A1 and GSTA1 are regulated by sulforaphane through different signal transduction pathways and the differences in the mechanisms of modulation of UGT1A1 transcription by sulforaphane and apigenin resulted in a synergistic effect between these two compounds in the induction of UGT1A1.
Carcinogenesis 2004 Sep
PMID:Interactions between sulforaphane and apigenin in the induction of UGT1A1 and GSTA1 in CaCo-2 cells. 1509 Apr 68

Colorectal cancer (CRC) is one of the most common malignancies in the Western world showing an increasing incidence, and has been associated with genetic and lifestyle factors. Individual susceptibility to CRC may be due partly to variations in detoxification capacity in the gastrointestinal tract. Genetic polymorphisms in detoxification enzymes may result in variations in detoxification activities, which subsequently might influence the levels of toxic/carcinogenic compounds, and this may influence the risk for CRC. To determine whether genetic polymorphisms in detoxification enzymes predispose to the development of CRC, 371 patients with sporadic CRC and 415 healthy controls were genotyped for polymorphisms in the important detoxification enzymes UDP-glucuronosyltransferase UGT1A1, UGT1A6, UGT1A7 and UGT1A8, and glutathione S-transferase GSTA1, GSTM1, GSTP1 and GSTT1. Patients and controls were all of Caucasian origin. DNA was isolated from either blood or tissue and tested by polymerase chain reaction followed by restriction fragment length polymorphism analyses. Logistic regression analyses showed significant age- and gender-adjusted risks for CRC associated with variant genotypes of UGT1A6 [OR 1.5, 95% (confidence interval) CI 1.03-2.3] and UGT1A7 (OR 2.4, 95% CI 1.3-4.6), whereas no associations were found between CRC and the other polymorphic genes as mentioned above. In conclusion, the data suggest that the presence of variant UGT1A6 and UGT1A7 genotypes with expected reduced enzyme activities, might enhance susceptibility to CRC.
Carcinogenesis 2004 Dec
PMID:Genetic polymorphisms in UDP-glucuronosyltransferases and glutathione S-transferases and colorectal cancer risk. 1531 94

Lack of functional telomeres can cause chromosomal aberrations. This type of genetic instability may promote tumorigenesis. We have investigated the association between mean telomere length in buccal cells (assessed with quantitative real-time PCR) and bladder cancer risk in a case-control study. Patients with bladder cancer displayed significantly shorter telomeres than control subjects (P = 0.001). Median telomere length ratio was 0.95 (range 0.53-3.2) for cases and 1.1 (0.51-2.4) for controls. Moreover, the adjusted odds ratio (OR) for bladder cancer was significantly increased in the quartile with the shortest telomere length OR = 4.5 [95% confidence interval (CI) 1.7-12]. It is known that oxidative stress, alkylation or UV radiation increases shortening of telomeres. Therefore, we also analyzed whether environmental and genetic factors associated with DNA damage, i.e. smoking and polymorphisms in the genes involved in the metabolism of genotoxic carcinogens (EPHX1, GSTA1, GSTM1, GSTP1, GSTT1, NAT1, NAT2 and NQO1) or DNA repair (APE1, NBS1, XPC, XPD, XRCC1, XRCC3 and XRCC4), could modify the association between telomere length and cancer risk. A clear effect of smoking and telomere length could be observed. Current smokers with short telomeres had more than six times as higher risk as non-smokers/former smokers with long telomeres (OR = 6.3, 95% CI 1.7-23). Lack of the biotransformation gene GSTM1 and short telomeres were associated with OR = 6.5 (95% CI 2.4-18), whereas homozygous carriers of 312Asn in the DNA repair gene XPD, with short telomeres, displayed an OR of 17 (95% CI 1.9-150). However, no significant interaction for cancer risk could be proven for telomere length, smoking and susceptibility genotypes of metabolizing and DNA-repairing genes.
Carcinogenesis 2005 Jul
PMID:Constitutional short telomeres are strong genetic susceptibility markers for bladder cancer. 1574 60

Dietary factors appear to be involved in the high incidence of prostate cancer in "Westernized" countries, implicating dietary carcinogens such as heterocyclic amines (HAs) in the initiation of prostate carcinogenesis. We examined 24 human prostate samples with respect to their potential for activation and detoxification of HAs and the presence of DNA adducts formed in vivo. Cytochromes P450 1B1, 3A4 and 3A5 were expressed at low levels (<0.1-6.2 pmol/mg microsomal protein). N-Acetyltransferase (NAT) activities, using p-aminobenzoic acid (NAT1) and sulfamethazine (NAT2) as substrates, were <5-5,500 and <5-43 pmol/min/mg cytosolic protein, respectively. Glutathione S-transferases (GSTs) P1, M2 and M3 were expressed at 0.038-1.284, 0.005-0.126 and 0.010-0.270 microg/mg cytosolic protein, respectively; GSTM1 was expressed in all GSTM1-positive samples (0.012-0.291 microg/mg cytosolic protein); and GSTA1 was expressed at low levels (<0.01-0.11 microg/mg cytosolic protein). Binding of N-hydroxy-PhIP to DNA in vitro occurred primarily by an AcCoA-dependent process (<1-54 pmol/mg/DNA), PAPS- and ATP-dependent binding being <1-7 pmol/mg DNA. In vivo, putative PhIP- or 4-aminobiphenyl-DNA adducts were found in 4 samples (0.4-0.8 adducts/10(8) bases); putative hydrophobic adducts were found in 6 samples (8-64 adducts/10(8) bases). Thus, the prostate appears to have low potential for N-hydroxylation of HAs but greater potential for activation of N-hydroxy HAs to genotoxic N-acetoxy esters. The prostate has potential for GSTP1-dependent detoxification of ATP-activated N-hydroxy-PhIP but little potential for detoxification of N-acetoxy-PhIP by GSTA1. However, there were no significant correlations between expression/activities and DNA adducts formed in vitro or in vivo, DNA adducts in vivo possibly reflecting carcinogen exposure.
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PMID:Expression of cytochromes P450 and glutathione S-transferases in human prostate, and the potential for activation of heterocyclic amine carcinogens via acetyl-coA-, PAPS- and ATP-dependent pathways. 1588 May 31


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