Human acetylator genotype: Relationship to colorectal cancer incidence and arylamine N-acetyltransferase expression in colon cytosol

Abstract

Polymorphic expression of arylamine N-acetyltransferase (EC 2.3.1.5) may be a differential risk factor in metabolic activation of arylamine carcinogens and susceptibility to cancers related to arylamine exposures. Human epidemiological studies suggest that rapid acetylator phenotype may be associated with higher incidences of colorectal cancer. We used restriction fragment length polymorphism analysis to determine acetylator genotypes of 44 subjects with colorectal cancer and 28 non-cancer subjects of similar ethnic background (i.e., approximately 25% Black and 75% White). The polymorphic N-acetyltransferase gene (NAT2) was amplified by the polymerase chain reaction from DNA templates derived from human colons of colorectal and non-cancer subjects. No significant differences in NAT2 allelic frequencies (i.e., WT, M1, M2, M3 alleles) or in acetylator genotypes were found between the colorectal cancer and non-cancer groups. No significant differences in NAT2 allelic frequencies were observed between Whites and Blacks or between males and females. Cytosolic preparations from the human colons were tested for expression of arylamine N-acetyltransferase activity. Although N-acetyltransferase activity was expressed for each of the arylamines tested (i. e., p-aminobenzoic acid, 4-aminobiphenyl, 2-aminofluorene, beta-naphthylamine), no correlation was observed between acetylator genotype and expression of human colon arylamine N-acetyltransferase activity. Similarly, no correlation was observed between subject age and expression of human colon arylamine N-acetyltransferase activity. These results suggest that arylamine N-acetyltransferase activity expressed in human colon is catalyzed predominantly by NAT1, an arylamine N-acetyltransferase that is not regulated by NAT2 acetylator genotype.(ABSTRACT TRUNCATED AT 250 WORDS)

Genetic polymorphisms ofp53 andGSTP1,but notNAT2,are associated with susceptibility to squamous-cell carcinoma of the esophagus

“…The NAT2 rapid acetylator has been associated with risk of colorectal cancer (Ilett et al, 1987), whereas the slow acetylator has been associated with bladder cancer in both heavy smokers and the general population (Brockmöller et al, 1996). However, other groups have not found associations with colorectal or bladder cancer (Spurr et al, 1995;Rodriguez et al, 1993). In the esophagus, the slow NAT2 acetylator was more susceptible to esophageal cancer in Japan (Morita et al, 1998).…”

N-Acetyltransferase 2 Phenotype May Be Associated with Susceptibility to Age-Related Cataract

“…Polymorphic aromatic amine NAT2 catalyzes the Nacetylation of aromatic amines and the metabolic activation of N-hydroxyarylamines (via O-acetylation) and N-hydroxy-N-acetylarylamines (via N, O-acetylation) to electrophilic intermediates that mutate DNA. 12 Arylamine chemicals inflict a number of toxicities including cancer. Metabolic activation (i.e., oxidation) is required in order to elicit the toxic actions.…”

N-acetyltransferase 2 gene polymorphism in patients with colorectal carcinoma

“…2 Arylamine N-acetyltransferases (EC 2.3.1.5) in humans catalyses the acetylation of arylamines derived from food to heterocyclic arylamine carcinogens. 3,4 Aromatic amines and hydrazine (N-acetylation) and N-hydroxy-aromatic and heterocyclic amines (O-acetylation) are both examples of acceptor substrates that, in general, are deactivated (N-acetylation) or activated (O-acetylation) by NAT1 and/or NAT2. NAT1 and NAT2 also catalyse the intramolecular N, O-acetyltransfer of N-hydroxy-N-acetylaromatic amines.…”