Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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.
 ...
PMID:The role of xenobiotic metabolizing enzymes in arylamine toxicity and carcinogenesis: functional and localization studies. 920 51

Aromatic amine acetylation has been recognized for many years as an important metabolic polymorphism in humans because of its relationship to disease. This system serves as a model in risk assessment because of its role in drug and carcinogen activation and detoxification and because of the case with which it is measured. However, possible interactions of NAT1-NAT2 phenotypes or genotypes illustrate the complexity of xenobiotic metabolism pathways. Moreover, the use of such information for risk assessment is further complicated by the association of the rapid phenotype with increased risk in colon cancer and the slow phenotype with increased risk in urinary bladder cancer. Before this biomarker can be effectively utilized as a significant predictor of individual risk, it will be necessary to identify specific sources of aromatic amine exposure and to characterize further the substrate specificity of NAT1 and NAT2 in relation to the multiplicity of enzyme variants occurring in human populations.
 ...
PMID:Acetylation as an indicator of risk. 925 59

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.
 ...
PMID:Polymorphisms in xenobiotic conjugation and disease predisposition. 1002 51

It has become clear that several polymorphisms of human drug-metabolizing enzymes influence an individual's susceptibility for chemical carcinogenesis. This review gives an overview on relevant polymorphisms of four families of drug-metabolizing enzymes. Rapid acetylators (with respect to N-acetyltransferase NAT2) were shown to have an increased risk of colon cancer, but a decreased risk of bladder cancer. In addition an association between a NAT1 variant allele (NAT*10, due to mutations in the polyadenylation site causing approximately two fold higher activity) and colorectal cancer among NAT2 rapid acetylators was observed, suggesting a possible interaction between NAT1 and NAT2. Glutathione S-transferases M1 and T1 (GSTM1 and GSTT1) are polymorphic due to large deletions in the structural gene. Meta-analysis of 12 case-control studies demonstrated a significant association between the homozygous deletion of GSTM1 (GSTM1-0) and lung cancer (odds ratio: 1.41; 95% CI: 1.23-1.61). Combination of GSTM1-0 with two allelic variants of cytochrome P4501A1 (CYP1A1), CYP1A1 m2/m2 and CYP1A1 Val/Val further increases the risk for lung cancer. Indirect mechanisms by which deletion of GSTM1 increases risk for lung cancer may include GSTM1-0 associated decreased expression of GST M3 and increased activity of CYP1A1 and 1A2. Combination of GST M1-0 and NAT2 slow acetylation was associated with markedly increased risk for lung cancer (odds ratio: 7.8; 95% CI: 1.4-78.7). In addition GSTM1-0 is clearly associated with bladder cancer and possibly also with colorectal, hepatocellular, gastric, esophageal (interaction with CYP1A1), head and neck as well as cutaneous cancer. In individuals with the GSTT1-0 genotype more chromosomal aberrations and sister chromatid exchanges (SCEs) were observed after exposure to 1,3-butadiene or various haloalkanes or haloalkenes. Evidence for an association between GSTT1-0 and myelodysplastic syndrome and acute lymphoblastic leukemia has been presented. A polymorphic site of GSTP1 (valine to isoleucine at codon 104) decreases activity to several carcinogenic diol epoxides and was associated with testicular, bladder and lung cancer. Microsomal expoxide hydrolase (mEH) is polymorphic due to amino acid variation at residues 113 and 139. Polymorphic variants of mEH were associated with hepatocellular cancer (His-113 allele), ovarian cancer (Tyr-113 allele) and chronic obstructive pulmonary disease (His-113 allele). Three human sulfotransferases (STs) are regulated by genetic polymorphisms (hDHEAST, hM-PST, TS PST). Since a large number of environmental mutagens are activated by STs an association with human cancer risk might be expected.
 ...
PMID:Polymorphisms of N-acetyltransferases, glutathione S-transferases, microsomal epoxide hydrolase and sulfotransferases: influence on cancer susceptibility. 1002 93

The acetylation polymorphism, discovered 40 years ago, holds a special place as one of the first described examples of a pharmacogenetic defect affecting xenobiotic biotransformation capacity in human populations. The genetically determined N-acetyltransferase activity is involved in activation/inactivation reactions of numerous xenobiotics. Therefore, it has been suggested that slow acetylator status may modify the individual responses to various chemicals. In humans, two genes, NAT1 and NAT2, are responsible for N-acetyltransferase activity. To date several allelic variants of both NAT1 and NAT2 have been detected, and it has been suggested that some of them modify individual susceptibility to cancer. Slow NAT2 acetylation capacity has been suggested as conferring increased risk of bladder, breast, liver and lung cancers, and decreased risk of colon cancer, whereas a prominent change in the NAT1 gene, putatively associated with increased NAT1 activity, has been suggested as increasing the risk of bladder and colon cancer and decreasing that of lung cancer. While three of the NAT2 variants have been shown to account for most of the slow NAT2 acetylator genotypes in Caucasians, less complete data are available on how the NAT1 variants modify NAT1 activity in vivo. This review discusses present knowledge on NAT polymorphisms, particularly in relation to individual cancer predisposition.
 ...
PMID:Polymorphic NATs and cancer predisposition. 1049 62

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.
 ...
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

Arylamine carcinogens and drugs are N-acetylated by cytosolic N-acetyltransferase (NAT), which uses acetyl-coenzyme A as a cofactor. NAT plays an initial role in the metabolism of these arylamine compounds. 2-Aminofluorene is one of the arylamine carcinogens which have been demonstrated to undergo N-acetylation in laboratory animals and humans. Our previous study showed that human cancer cell lines (colon cancer, colo 205; liver cancer, Hep G2; bladder cancer, T24; leukemia, HL-60; prostate cancer, LNCaP; osteogenic sarcoma, U-2 OS; malignant melanoma, A375.S2) displayed NAT activity, which was affected by aloe-emodin in human leukemia cells. The purpose of this study was to determine whether aloe-emodin could affect the enzyme activity and gene expression of NAT at the mRNA and protein levels in malignant human melanoma A375.S2 cells. The results showed that aloe-emodin inhibited NAT1 activity (decreased N-acetylation of 2-aminofluorene) in intact cells in a dose-dependent manner. The effect of aloe-emodin on NAT1 at the protein level was determined by Western blotting and the mRNA levels were examined by polymerase chain reaction (PCR) and cDNA microarray. These results clearly indicate that aloe-emodin inhibits the mRNA expression and enzyme activity of NAT1 in A375.S2 cells.
 ...
PMID:Effect of inhibition of aloe-emodin on N-acetyltransferase activity and gene expression in human malignant melanoma cells (A375.S2). 1631 33

Colorectal cancer appears to have rapidly increased over the past two decades in Korea. Environmental factors, characterized by a western life style, seem to be closely related to the increased risk of colorectal cancer. Higher intakes of meat, a lower vegetable intake, a lack of physical activity, obesity, and alcohol drinking have been suggested to be risk factors for colorectal cancer in the numerous epidemiologic studies. Several specific associations have also been observed between genetic polymorphisms and colorectal cancer. Moreover, it has been postulated that environmental factors and a genetic predisposition work in concert in colorectal cancer development. A stronger association between red meat intake and colorectal cancer among those with rapid acetylators at either the NAT1 or NAT2 locus was reported, particularly for colorectal cancer associated with K-ras mutations. The protective effect of the homozygous variant TT form of the MTHFR genotype on the risk of colon cancer seems to be modified by the level of methyl diets, i.e., by folate, which has a protective effect, or conversely by alcohol. The insulin-related pathway, which possibly explains at a mechanistic level the effect of physical activity and obesity on colon cancer, appears to be a common denominator in colon cancer and in other metabolic disorders, such as diabetes mellitus and dyslipidemia. Hyperinsulinemia has been proposed as an explanation for the association between a Western lifestyle and colon cancer risk. Further studies, that incorporate both genetic and environmental factors, are needed to fully explain and identify the underlying pathway of colorectal carcinogenesis.
 ...
PMID:Molecular epidemiology of colon cancer. 2039 47