UMLS:C0699790 - FACTA Search

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Query: UMLS:C0699790 (colon cancer)
28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In both animal models and humans, the first and obligatory step in the activation of arylamines is N-hydroxylation. This pathway is primarily mediated by the phase-I enzymes CYP1A1, CYP1A2 and CYP4B1. In the presence of flavonoids such as alpha-naphthoflavone and flavone, both CYP3A4 and CYP3A5 have also been shown to play a minor role in the activation of food-derived heterocyclic amines. The further activation of N-hydroxyarylamines by phase-II metabolism can involve both N, O-acetylation and N, O-sulfonation catalyzed by N-acetyltransferases (NAT1 and NAT2) and sulfotransferases, respectively. Using an array of techniques, we have been unable to detect constitutive CYP1A expression in any segments of the human gastrointestinal tract. This is in contrast to the rabbit where CYP1A1 protein was readily detectable on immunoblots in microsomes prepared from the small intestine. In humans, CYP3A3/3A4 expression was detectable in the esophagus and all segments of the small intestine. Northern blot analysis of eleven human colons showed considerable heterogeneity in CYP3A mRNA between individuals, with the presence of two mRNA species in some subjects. Employing the technique of hybridization histochemistry (also known as in situ hybridization), CYP4B1 expression was observed in some human colons but not in the liver or the small intestine. Hybridization histochemistry studies have also demonstrated variable NAT1 and NAT2 expression in the human gastrointestinal tract. NAT1 and NAT2 mRNA expression was detected in the human liver, small intestine, colon, esophagus, bladder, ureter, stomach and lung. Using a general aryl sulfotransferase riboprobe (HAST1), we have demonstrated marked sulfotransferase expression in the human colon, small intestine, lung, stomach and liver. These studies demonstrate that considerable variability exists in the expression of enzymes involved in the activation of aromatic amines in human tissues. The significance of these results in relation to a role for heterocyclic amines in colon cancer is discussed.
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PMID:The role of xenobiotic metabolizing enzymes in arylamine toxicity and carcinogenesis: functional and localization studies. 920 51

Low activity of arylamine N-acetyltransferase 2 (slow NAT2) was consistently associated with urinary bladder cancer risk. The increased cancer risk attributable to slow NAT2 was more significant when taking gene-environment interactions and gene-gene interactions into account. In urinary bladder, slow NAT2 was no risk factor in subjects who never smoked but became increasingly relevant with increasing lifetime dose of tobacco smoke expressed by an odds ratio of 2.7 for slow NAT2 in extensive smokers. The functional impact of some arylamine N-acetyltransferase 1 variants is controversial. It was published that the NAT1 allele 10 was associated with high enzyme activity and that there was an overrepresentation of carriers of NAT1*10 in bladder and colon cancer, but we could only detect a moderately elevated activity of NAT1*10 and an underrepresentation of fast NAT1 alleles in bladder cancer. Recently, a C/A-polymorphism in intron 1 of cytochrome P450 1A2 was associated with high inducibility and persons with this high inducibility variant were overrepresented in bladder cancer, but only if they were smokers or if they had slow NAT2 genotypes. Numerous studies have shown that glutathione S-transferase M1 deficiency (GSTM1*0/0) increases the risk for lung and bladder cancer but the overall risk attributable to GSTM1*0/0 was only around 1.3 according to meta-analyses. The GSTM1*0/0 genotype appears to be the best established metabolic susceptibility factor. Several independent experimental approaches showed that GSTM1 decreases mutagenicity of reactive epoxides and it was shown that carriers of GSTM1*0/0 were at increased risk for several types of cancer and other diseases. There are also studies which showed no effects of GSTM1, a result which is compatible with the assumption that GSTM1*0/0 is a susceptibility factor of moderate strength. GSTM1*0/0 may, however, become a dominant risk factor in certain gene-gene combinations such as the combination with highly active CYP1A1 gene variants or in combination with specific types of exposure. Specific precautions have to be taken in the design of molecular epidemiological studies on risk factors with moderate strength; some requirements for high quality molecular epidemiological studies will be discussed in this article. Molecular epidemiology is an increasingly powerful approach to understand carcinogenesis and may be used in the future to individualize cancer prevention strategies.
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PMID:Polymorphisms in xenobiotic conjugation and disease predisposition. 1002 51

Several polymorphic cytochrome P-450 and glutathione S-transferase (GST) enzymes are involved in the activation and detoxification of many potential carcinogens and may therefore be important in susceptibility to cancer induction. CYP1A1 MspI, GSTM1, and GSTT1 are polymorphic enzymes and some alleles have been correlated with an increased risk of developing some cancers. In the present study, we examined possible associations between genetic polymorphisms of CYP1A1 MspI, GSTM1, and GSTT1 and colon cancer in a United Kingdom population. An excess of CYP1A1 MspI, and GSTM1 null genotypes was observed amongst colon cancer patients, although this did not reach the level of statistical significance. We found no significant increase in the risk of colon cancer for either CYP1A1 MspI (OR = 1.39; 95%CI: 0.46-4.21) or GSTM1 null (OR = 1.41; 95%CI: 0.76-3.01) genotypes. Individuals with GSTT1 null genotype had no association with colon cancer (OR = 0.42; 95%CI: 0.09-2.02). No significant association was observed in the site of colon cancer (proximal vs. distal). This study suggests that the polymorphisms of CYP1A1 MspI, GSTM1, and GSTT1 are not associated with a significant risk of developing colon cancer in a United Kingdom population.
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PMID:Genetic polymorphisms in the cytochrome P450 1A1, glutathione S-transferase M1 and T1, and susceptibility to colon cancer. 1221 May 2

Rat small intestinal epithelial cells and human colon adenocarcinoma cells cultured on Matrigel expressed the differentiation specific enzyme, sucrase-isomaltase, as determined by indirect immunofluorescence. Rat small intestinal epithelial cells, rat colonocytes, and human colon adenocarcinoma cells developed an altered morphology when cultured on Matrigel and became apoptotic within 24-48 h. Benzo[a]pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin caused a 2- and 5-fold induction, respectively, of ethoxyresorufin-o-deethylase activity in rat small intestinal epithelial cells cultured on Matrigel. Benzo[a]pyrene- or 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced ethoxyresorufin-o-deethylase activity in rat small intestinal epithelial cells cultured on plastic was not detected. 2,3,7,8-tetrachlorodibenzo-p-dioxin treatment caused a 14-fold induction of transfected, rat CYP1A1-promoter-luciferase activity in rat small intestinal epithelial cells cultured on Matrigel. Benzo[a]pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin treatment induced ethoxyresorufin-o-deethylase activity by 6- and 1.6-fold, respectively in rat colonocytes cultured on Matrigel. Induction of ethoxyresorufin-o-deethylase activity was not observed in rat colonocytes cultured on plastic. CYP1A1-promoter-luciferase activity was induced 3-fold by 2,3,7,8-tetrachlorodibenzo-p-dioxin in rat colonocytes cultured on Matrigel. Induction of CYP1A1-promoter-luciferase activity in rat small intestinal epithelial cells or rat colonocytes cultured on plastic was not observed. Ethoxyresorufin-o-deethylase activity in human colon adenocarcinoma cells, cultured on either plastic or Matrigel, was induced 7-fold by benzo[a]pyrene. 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced ethoxyresorufin-o-deethylase activity was 2-fold greater in human colon adenocarcinoma cells cultured on Matrigel compared to cells cultured on plastic. Extracellular matrix-mediated differentiation and apoptosis of intestinal cells provide in vitro systems for study of the regulation of CYP1A1 expression, carcinogen activation in the gut and mechanism(s) of apoptosis of colon cancer cells.
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PMID:Differentiation-dependent induction of CYP1A1 in cultured rat small intestinal epithelial cells, colonocytes, and human colon carcinoma cells: basement membrane-mediated apoptosis. 1221 Jul 51

Cytochrome P-450 (CYP) is involved in the activation and metabolism of polycyclic aromatic hydrocarbons in tobacco products. The authors evaluated the association of two polymorphisms in the CYP1A1 gene--the noncoding Msp I polymorphism in the 3'-untranslated region and the Ile462Val polymorphism in exon 7--with colon and rectal cancer. The authors used data from two incident case-control studies of colon cancer (1,026 cases and 1,185 controls) and rectal cancer (820 cases and 1,036 controls) conducted in California and Utah (1991-2002). CYP1A1 genotype was not associated with colon or rectal cancer. Having GSTM1 present, a CYP1A1 variant allele, and the rapid-acetylator NAT2 imputed phenotype was associated with increased risk of colon cancer (odds ratio = 1.7, 95% confidence interval: 1.2, 2.3). Among men, the greatest colon cancer risk was observed for having any CYP1A1 variant allele and currently smoking (odds ratio = 2.5, 95% confidence interval: 1.3, 4.8; Wald chi(2)test: p < 0.01). Assessment of GSTM1 and CYP1A1 and rectal cancer in men showed a twofold elevation in risk for more than 20 pack-years of smoking, except among those with GSTM1 present who had a variant CYP1A1 allele. These data support the association between smoking and colon and rectal cancer. Smoking may have a greater impact on colorectal cancer risk based on CYP1A1 genotype; this might further be modified by GSTM1 for rectal cancer risk.
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PMID:CYP1A1, cigarette smoking, and colon and rectal cancer. 1549 36

We hypothesized that the risk of colorectal cancer associated with meat preparation methods producing heterocyclic amines or polycyclic aromatic hydrocarbons is modified by the CYP1A1 genotype alone or in combination with the GSTM1 genotype or the NAT2 imputed phenotype. A total of 952 rectal cancer cases and 1205 controls (between September 1997 and February 2002) and 1346 colon cancer cases and 1544 controls (between October 1991 and September 1994) from Utah and Northern California were recruited from a population-based case-control study. Detailed interviews ascertained lifestyle, medical history, and diet and we extracted DNA from whole blood. Risk of colorectal cancer decreased among men with the CYP1A1 *2 any variant genotype and the lowest intake of poultry and men and women with high use of white meat drippings. Risk increased among men with the CYP1A1 *1 (no variant) allele and high white meat mutagen index, but decreased among those with the CYP1A1 *2 genotype. Risk increased with a high white meat mutagen index among women with the CYP1A1 *2 genotype and the GSTM1 present genotype. Risk of colorectal cancer decreased with the CYP1A1 *2 genotype, the NAT2 slow phenotype, and the use of white meat or its drippings. The association of risk for colorectal cancer and selected red and white meat mutagen indices and the use of white meat drippings, or fried white meat variables was more evident within select combinations of the CYP1A1 genotype and either the GSTM1 genotype or NAT2 than with the CYP1A1 alone. Genetic susceptibility may modify the associations of some meat or meat preparation factors with the risk of colorectal cancer.
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PMID:The CYP1A1 genotype may alter the association of meat consumption patterns and preparation with the risk of colorectal cancer in men and women. 1567 Dec 10

Organosulfur compounds (OSCs) derived from garlic have been studied for the ability to inhibit experimental cancer in various animal models, primarily through modification of carcinogen detoxification enzymes, such as cytochrome P450 (CYP) enzymes. OSCs vary in structural and physical properties, and a detailed analysis of these properties has not been performed with respect to their ability of inhibit chemically-induced colon cancer development. Gastric intubation of rats with a single dose of 200 mg/kg diallyl sulfide (DAS), diallyl disulfide (DADS), and allyl methyl sulfide (AMS) decreased hepatic CYP2E1 protein by 45%, 25% and 47%, respectively, and this inhibition was sustained after 1, 4 and 8 weeks of treatment by these compounds. Dipropyl sulfide (DPS), dipropyl disulfide (DPDS), propyl methyl sulfide (PMS) and S-allylcysteine (SAC) did not inhibit hepatic CYP2E1 protein expression, nor did any of the OSCs affect CYP2E1 mRNA levels. A single dose of 200 mg/kg DAS and AMS increased hepatic CYP1A2 protein (but not mRNA) by 282% and 70%, and DAS increased CYP1A1 protein levels by 684%. Daily treatment for 1, 4 and 8 weeks with 200 mg/kg DAS and AMS resulted in time-dependent increases in hepatic CYP1A1 and CYP1A2 protein levels to a maximum of 600% and 50% for DAS, and 1600% and 240% for AMS after 8 weeks. Dosing with 200 mg/kg of each of the OSCs used in this study increased hepatic CYP3A2 protein levels at all time points. Dosing for 8 weeks with 200 mg/kg DAS, but not AMS or lower doses of DAS, induced bile duct obstruction and focal areas of necrosis. These results indicate that OSCs present in garlic, including DAS and AMS, may be beneficial in inhibiting chemically-induced colon cancer, but that longer dosing with higher concentrations of DAS may elicit minor hepatic toxicity.
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PMID:Modulation of cytochrome P450 enzymes by organosulfur compounds from garlic. 1600 Feb 31

Estrogen replacement therapy is associated with a reduced risk of colon cancer. Therefore, we evaluated the following ten estrogen metabolism-associated single-nucleotide polymorphisms (SNPs) by sequencing-on-chip technology using solid-phase polymerase chain reaction (PCR) on oligonucleotide microarrays: catechol-O-methyltransferase (COMT) Val158Met G-->A, 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17) vlV A-->C, cytochrome P-450 (CYP) 17 A2 allele T-->C, CYP1A1 MspI RFLP T-->C, CYP1A1 Ile462Val A-->G, CYP19 Arg264Cys C-->T, CYP19 C1558T C-->T, CYP 1B1 Leu432Val, CYP1B1 Asn453Ser, and estrogen receptor (ER) alpha IVS1 -401-->C in 76 patients with a family history of colon cancer and 722 healthy controls. Using stepwise logistic regression models, we found that none of the investigated SNPs is associated with a family history of colon cancer in a univariate and multivariate logistic regression model. In addition, when all two-way interactions of the investigated SNPs were ascertained, no significant interactions between SNPs were observed. In conclusion, we found no association between the carriage of one or multiple SNPs of the estrogen metabolism and a family history of colon cancer.
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PMID:Ten polymorphisms of estrogen-metabolizing genes and a family history of colon cancer--an association study of multiple gene-gene interactions. 1620 20

The incidence of colon cancer increases with age, and this may be related to altered metabolism and disposition of carcinogens. One such carcinogen implicated in colon cancer is the heterocyclic amine found in well done meat, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). The purpose of these studies was to determine whether the disposition and metabolism of IQ changes with age, comparing young (3-month) and old (22- to 24-month) male F344 rats. Animals were treated with vehicle or beta-naphthoflavone (BNF), an inducer of drug-metabolizing cytochromes P450. Disposition and metabolism of IQ were determined after i.p. injection of radiolabeled IQ. Urinary IQ metabolites were identified and quantitated by high-performance liquid chromatography and mass spectroscopy. In BNF-treated animals, total radiolabeled IQ excretion by old rats was less than half that of young rats. Binding of radiolabeled IQ metabolites by the old kidney was 10 times higher than that of the young. There were no age differences in intestinal and hepatic binding. There was a significant age-related increase in IQ conjugation to glucuronic acid and a decrease in conjugation to sulfate regardless of treatment. The induction of renal CYP1A1, a major P450 involved in IQ metabolism, by BNF did not change with age. Changes in IQ metabolism with age along with altered renal function may contribute to the decreased urinary excretion and increased renal binding of IQ and/or its metabolites seen in the old animals.
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PMID:Metabolism of a heterocyclic amine colon carcinogen in young and old rats. 1725 6

Sulindac is a nonsteroidal antiinflammatory drug that has been demonstrated to be a potent chemopreventive agent against colorectal cancer in both human and animal models. In vivo, sulindac may be reversibly reduced to the active antiinflammatory compound, sulindac sulfide, or irreversibly oxidized to sulindac sulfone. Sulindac has also been shown to inhibit polycyclic aromatic hydrocarbon (PAH)-induced cancer, but the molecular mechanisms of its antitumor effect remain unclear. In this study, we investigated the effects of sulindac and its metabolites on the expression of enzymes that metabolize and detoxify PAHs in 2 human colon cancer cell lines, LS180 and Caco-2. Sulindac and sulindac sulfide induced a sustained, concentration-dependent increase in CYP enzyme activity as well as an increase in the mRNA levels of CYP1A1, CYP1A2 and CYP1B1. Sulindac and sulindac sulfide induced the transcription of the CYP1A1 gene, as measured by the level of heterogeneous nuclear CYP1A1 RNA and verified by the use of actinomycin D as a transcription inhibitor. Chromatin immunoprecipitation assays demonstrated that sulindac and sulindac sulfide also increased the nuclear level of activated aryl hydrocarbon receptor, the transcription factor which mediates CYP expression. Additionally, sulindac and both metabolites increased the activity and mRNA expression of the carcinogen detoxification enzyme NAD(P)H:quinone oxidoreductase, as well as the expression of UDP-glucuronosyltransferase mRNA. These results show an overall upregulation of carcinogen metabolizing enzymes in colon cancer cells treated with sulindac, sulindac sulfide and sulindac sulfone that may contribute to the established chemoprotective effects of these compounds.
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PMID:Sulindac and its metabolites induce carcinogen metabolizing enzymes in human colon cancer cells. 1798 43

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