Aromatic amine acetyltransferase as a marker for colorectal cancer: Environmental and demographic associations

Wohlleb, James C.; Hunter, Carolyn F.; Blass, Baxter; Kadlubar, Fred F.; Chu, David Z. J.; Lang, Nicholas P.

doi:10.1002/ijc.2910460107

Cited by 79 publications

(31 citation statements)

References 28 publications

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“…However, few diseases have consistently demonstrated a relationship between phenotype and risk. For example, several studies have implicated the rapid phenotype as an increased risk factor for colon cancer, [95][96][97] whereas others have been unable to confirm this finding. [98][99][100] Geographical differences, ethnicity, lack of study power, dietary differences and differences in other risk factors between study groups have been suggested as reasons for variable results from indewww.nature.com/tpj pendent laboratories.…”

Section: Nat and Diseasementioning

confidence: 99%

Pharmacogenetics of the arylamine N-acetyltransferases

et al. 2002

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The arylamine N-acetyltransferases (NATs) are involved in the metabolism of a variety of different compounds that we are exposed to on a daily basis. Many drugs and chemicals found in the environment, such as those in cigarette smoke, car exhaust fumes and in foodstuffs, can be either detoxified by NATs and eliminated from the body or bioactivated to metabolites that have the potential to cause toxicity and/or cancer. NATs have been implicated in some adverse drug reactions and as risk factors for several different types of cancers. As a result, the levels of NATs in the body have important consequences with regard to an individual's susceptibility to certain druginduced toxicities and cancers. This review focuses on recent advances in the molecular genetics of the human NATs.

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Section: Nat and Diseasementioning

confidence: 99%

Pharmacogenetics of the arylamine N-acetyltransferases

et al. 2002

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“…Greater susceptibility to this disease has long been associated with dietary factors, including consumption of well-done red meats (12) and of cured and smoked meats (13). During the cooking process, pyrolysis of meat liquids can result in the formation of mutagenic and carcinogenic heterocyclic amines (14), such as 2-amino-3-methylimidazo[4,5-J]quinoline (IQ), 2-amino-3,8-dimethylimidazo-[4,5-flquinoxaline (MeIQx), 2-amino-1-methyl-6-phenyHmidazo [4,5-b]pyridine (PhIP), and 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1).…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms for Aromatic Amine Metabolism in Humans: Relevance for Human Carcinogenesis

Kadlubar¹,

Butler²,

Kaderlik³

et al. 1992

Environmental Health Perspectives

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The metabolic pathways associated with carcinogenic aromatic amines in humans provide an excellent example of polymorphisms that appear to be relevant to human carcinogenesis. In this regard, the N-acetylation of arylamines and the O-acetylation of their N-hydroxy metabolites are catalyzed preferentially by a genetically polymorphic acetyltransferase, high activity of which has been correlated with decreased risk for urinary bladder cancer and increased susceptibility to colorectal cancer. Cytochrome P450IA2, the principal liver enzyme involved in aromatic amine N-oxidation, exhibits a wide interindividual variation that appears trimodal in several populations and is clearly inducible by cigarette smoking and probably other host factors as well. UDP-Glucuronosyltransferases, which catalyze the N-glucuronidation of N-hydroxyarylamines and are likely to be responsible for their transport to the colon, show widely varied but unimodal distributions in humans. In contrast, human liver sulfotransferase activity forN-hydroxyarylamines, which would be expected to decrease their transport through the circulation, is catalyzed by a polymorphic enzyme(s) that is expressed at higher levels in blacks, as compared to whites, and could contribute to their relatively lower incidence of urinary bladder cancer. Peroxidative activation of aromatic amines can also occur, especially from prostaglandin H synthase in the urinary bladder and myeloperoxidase in the lungs of cigarette smokers, and both show considerable individual variability, apparently due to the extent of tissue inflammation. In a pilot study, we have examined two of these polymorphisms, acetyltransferase and cytochrome P450IA2, in colorectal cancer/ polyp cases (n = 38) and controls (n = 100) and found that individuals who are both rapid acetylators and rapid N-oxidizers are indeed more prevalent (p < 0.008) among cases (37%) than among controls (16%).

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“…However, results from a number of studies show only weak and inconsistent associations with disease susceptibility. N-acetyltransferase 2 (NAT-2) polymorphism may be implicated in susceptibility to colon cancer (Lang et al, 1986;Wohlleb et al, 1990;Illett et al, 1994;Probst-Hensch et al, 1995), but there is evidence that its relationship may be by linkage with other genes rather than causally (Hubbard et al, 1997).We have used a polymerase chain reaction (PCR) strategy to investigate whether polymorphisms in the microsomal epoxide hydrolase gene (mEPHX) (Hassett et al, 1994) have any relationship to colon cancer. The enzyme is expressed in many tissues, including colon and liver.…”

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Microsomal epoxide hydrolase gene polymorphism and susceptibility to colon cancer

et al. 1998

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The colon is subject to oxidative and free radical damage by both products of endogenous metabolism and bacterial fermentation within the gut lumen. These injurious stimuli may cause cell damage or cell death or even lead to mutations, resulting in tumour initiation and progression. Colon cancer is a common disease, with the highest incidence in developed countries. The aetiology is unknown, but in addition to diet and cigarette smoking (Giovannucci and Willett, 1994) there is a complex polygenic background that determines individual susceptibility to disease. There is currently much interest in the roles of oncogenes, tumoursuppressor genes and mismatch repair enzymes in colon cancer (Tomlinson et al, 1997). In addition, interindividual variation in the ability to dispose of reactive xenobiotics catalysed by glutathione S-transferases GST-M1 and GST-T1 has been investigated (Lang et al, 1986;Strange et al, 1991;Zhong et al, 1993;Chenevix-Trench et al, 1995). However, results from a number of studies show only weak and inconsistent associations with disease susceptibility. N-acetyltransferase 2 (NAT-2) polymorphism may be implicated in susceptibility to colon cancer (Lang et al, 1986;Wohlleb et al, 1990;Illett et al, 1994;Probst-Hensch et al, 1995), but there is evidence that its relationship may be by linkage with other genes rather than causally (Hubbard et al, 1997).We have used a polymerase chain reaction (PCR) strategy to investigate whether polymorphisms in the microsomal epoxide hydrolase gene (mEPHX) (Hassett et al, 1994) have any relationship to colon cancer. The enzyme is expressed in many tissues, including colon and liver. Polymorphisms of mEPHX may have functional significance. There is variation in exon 3, where a T to C alteration changes tyrosine residue 113 to histidine and is associated with lower enzyme activity when expressed in vitro. By contrast, A to G transition in exon 4 changes histidine residue 139 to arginine and produces increased enzyme activity. The effect of combining the alleles has not been established. The activity of mEPHX varies more than 50-fold in Caucasians (Omiecinski et al, 1993). This variation of activity is, thus, due to a combination of genetic polymorphism, transcriptional and post-transcriptional control of gene expression. MATERIALS AND METHODS Controls and cancer casesControl blood samples (n = 203) were obtained anonymously from the Scottish National Blood Transfusion Service. These were Caucasian individuals aged between 18 and 65 years with equal sex distribution. This group has been previously described (Cantlay et al, 1994) and was drawn from the same geographical area as the cancer study group. The presence of colorectal neoplasia was not specifically excluded, but all patients were healthy. Peripheral blood from patients with colorectal cancer was collected from a consecutive series of operable colorectal cancer cases after surgery in four local hospitals between 1988 and 1993 (n = 101). Cancer patient dataCancer diagnosis was confirmed histopathologically...

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Aromatic amine acetyltransferase as a marker for colorectal cancer: Environmental and demographic associations

Cited by 79 publications

References 28 publications

Pharmacogenetics of the arylamine N-acetyltransferases

Pharmacogenetics of the arylamine N-acetyltransferases

Polymorphisms for Aromatic Amine Metabolism in Humans: Relevance for Human Carcinogenesis

Microsomal epoxide hydrolase gene polymorphism and susceptibility to colon cancer

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