Acetylator Genotype-dependent Expression of Arylamine N-Acetyltransferase in Human Colon Cytosol from Non-Cancer and Colorectal Cancer Patients

Abstract

Human epidemiological studies suggest an association between rapid acetylator phenotype and colorectal cancer. Acetylator genotype-dependent expression by the human colon of arylamine N-acetylation capacity, catalyzed by acetyl coenzyme A-dependent N-acetyltransferase(s) (EC 2.3.1.5) (NAT), may be an important risk factor in the initiation of colorectal cancer. Human colon cytosols from 48 fresh surgical samples were investigated for NAT activity toward p-aminobenzoic acid and the arylamine carcinogens 4-aminobiphenyl, 2-aminofluorene, and β-naphthylamine. Apparent V_max determinations of NAT activity toward these substrates indicated that 40 of these colons segregated into 3 distinct phenotypes. The distribution of the patients into rapid (5), intermediate (18), or slow (17) acetylators is a ratio that is not significantly different from the expected Hardy-Weinberg distribution of 3:16:21 (χ² = 2.206, P = 0.363). Significantly greater mean apparent V_max levels were found in colons from rapid as compared to intermediate acetylators (1.5-3-fold) (P < 0.001) and intermediate as compared to slow (2.5–3-fold) (P < 0.005) acetylator phenotypes for the four arylamine substrates. Apparent K_m determinations indicated that human colon NAT from rapid acetylators had a significantly lower affinity for the arylamine substrates (P < 0.05) compared to intermediate or slow acetylator groups. No difference in apparent K_m was detected for the cofactor acetyl coenzyme A between the three acetylator phenotypes. The colon samples were also tested for cytosolic N-hydroxy-2-acetylaminofluorene sulfotransferase activity and found to be monomorphically distributed for this enzyme activity. Of the 40 colon samples, 37 were from individuals of known pathology, 25 with colorectal cancer and 12 with no diagnosed neoplasia. Comparisons between mean apparent V_max and mean apparent K_m levels for each of the acetylator phenotypes indicated no significant differences between non-cancer and colorectal cancer patients. The distribution of rapid, intermediate, and slow acetylator phenotypes among the colon samples derived from colorectal cancer patients was precisely that predicted from published frequencies for the rapid and slow acetylator allele in Americans of African and European ancestry.