Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.5.7.1 (methylenetetrahydrofolate reductase)
 2,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The epidemiology and molecular biology of colorectal cancer are reviewed with a view to understanding their interrelationship. Risk factors for colorectal neoplasia include a positive family history, meat consumption, smoking, and alcohol consumption. Important inverse associations exist with vegetables, nonsteroidal anti-inflammatory drugs (NSAIDs), hormone replacement therapy, and physical activity. There are several molecular pathways to colorectal cancer, especially the APC (adenomatous polyposis coli)-beta-catenin-Tcf (T-cell factor; a transcriptional activator) pathway and the pathway involving abnormalities of DNA mismatch repair. These are important, both in inherited syndromes (familial adenomatous polyposis [FAP] and hereditary nonpolyposis colorectal cancer [HNPCC], respectively) and in sporadic cancers. Other less well defined pathways exist. Expression of key genes in any of these pathways may be lost by inherited or acquired mutation or by hypermethylation. The roles of several of the environmental exposures in the molecular pathways either are established (e.g., inhibition of cyclooxygenase-2 by NSAIDs) or are suggested (e.g., meat and tobacco smoke as sources of specific blood-borne carcinogens; vegetables as a source of folate, antioxidants, and inducers of detoxifying enzymes). The roles of other factors (e.g., physical activity) remain obscure even when the epidemiology is quite consistent. There is also evidence that some metabolic pathways, e.g., those involving folate and heterocyclic amines, may be modified by polymorphisms in relevant genes, e.g., MTHFR (methylenetetrahydrofolate reductase) and NAT1 (N-acetyltransferase 1) and NAT2. There is at least some evidence that the general host metabolic state can provide a milieu that enhances or reduces the likelihood of cancer progression. Understanding the roles of environmental exposures and host susceptibilities in molecular pathways has implications for screening, treatment, surveillance, and prevention.
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PMID:Colorectal cancer: molecules and populations. 1130 47

Environmental factors such as smoking cigarette, diets and alcohol may interact with genetic factors, which put one individual at a greater or lesser risk of a particular cancer than another. Advances in molecular biology have allowed many allelic variants of several drug metabolizing enzymes so that individuals with the susceptible genotypes can be determined easily. Many pieces of research have focused on the relationship between the distribution of polymorphic variants of different forms of the metabolic enzymes and colorectal cancer susceptibility because of importance roles of the metabolic enzymes in the activation of many procarcinogens or chemicals. In this respect five groups of the metabolic enzymes, cytochrome P450 (CYP) 1A1/CYP1A2, glutathione S-transferases (GSTs), N-acetyltransferases (NATs), aldehyde dehydrogenase 2 (ALDH2) and methylenetetrahydrofolate reductase (MTHFR), have been discussed here. A positive association between development of colorectal cancer and the mutant homozygous genotype in Msp1 polymorphism of CYP1A1 gene has been reported in Japanese in Hawaii. The relation between genetic polymorphisms in GSTs and cancer risk has also taken an interest. At least nine studies have demonstrated the relation between the GST polymorphisms and colorectal cancer. Two of these studies suggested an increased risk of approximately 2-fold among those with the GSTM1 null genotype, while others found no risk increase. None of these studies examined the combined effect of CYP1A1 and GST polymorphisms. Either NAT2 or CYP1A2 alone have been slightly associated with colorectal cancer. When CYP1A2 and NAT2 phenotype were combined, a significant increased risk (odds ratio of 2.8) was seen among well done meat consumers with the rapid-rapid phenotype. Two published studies have found that the risk of colorectal cancer can be enhanced (2-3 fold) in alcohol drinkers with heterozygous genotype of ALDH2 in two Japanese populations recently. Findings from three published studies suggested that the mutant genotype of MTHFR inversely slightly associated with colorectal cancer. Although some of genetic polymorphisms discussed here have not shown statistically significant increase/decrease in risk, individuals with differing genotypes may have different susceptibilities to colorectal cancer, based on environmental factors. Further studies are needed to identify risk groups more specific and to determine factors of importance in colorectal cancer development.
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PMID:Genetic polymorphism of enzymes involved in xenobiotic metabolism and the risk of colorectal cancer. 1105 19

Cholangiocarcinoma (CCA) is the most common cancer in endemic areas of liver fluke infection. Although the liver fluke is recognized as a carcinogenic agent in cholangiocarcinogenesis, other factors may play important roles in bringing about the high prevalence of the cancer in populations of this region. Drug metabolizing enzymes (DME) are essential for detoxification of toxic and carcinogenic chemicals. Moreover, DME can play an alternative role by activating chemicals to more toxic metabolites. The large variation of DME activity among individuals is partly due to polymorphism of the genes encoding enzymes. Defective or variant alleles of DME genes may modify the risk of cancer in those who are exposeed to carcinogenic agents. The focus in this review is on DME genes which have been reported to be associated with CCA risk. These include CYP1A2, arylamine- N-acetyltransferase-1 (NAT1) and NAT2, NADPH-quinone oxidorecutase-1 (NQO1), glutathione-S-transferase M1 (GSTM1), GSTT1, GSTO1 and methylenetetrahydrofolate reductase (MTHFR). Mutant alleles which have been reportedly associated with an increased risk include CYP1A2*1F, GSTT1 null, GSTO1 and MTHFR 677C>T, whereas, slow NAT2 and NQO1*2 decrease risk and NAT1 variants and GSTM1 null have no effect. These genes modify the risk of cancer potentially by interaction and exposure with certain environmental conditions, thereby altering the metabolism of causative agents.
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PMID:Genetic polymorphism of drug metabolizing enzymes in association with risk of bile duct cancer. 2348 Jul 67