Distribution of acetyltransferase activities in the intestines of rapid and slow acetylator rabbits

Abstract

Epidemiological studies have shown that there is a significantly greater proportion of the rapid acetylator phenotype in patients with colorectal tumors than in controls; phenotype-related differences in bioactivation of dietary or environmental amines in the intestinal epithelium have been suggested as a mechanism for this effect. In the present study, we have used hepatic and intestinal cytosols to compare N-acetyltransferase (NAT1 and NAT2), O-acetyltransferase (OAT) and arylhydroxamic acid N,O-acyltransferase (AHAT) distribution in rapid and slow acetylator rabbits. The ratio (rapid/slow) for p-aminobenzoic acid acetylation (a selective substrate for NAT1) was 6 in liver, 1.7-2 in small intestine and 1.3-1.5 in large intestine while the ratio of sulfamethazine acetylation (a selective substrate for NAT2) was 150 in liver, 16-22 in small intestine and 1.8-2.5 in large intestine. The ratios (rapid/slow) for DNA binding of N-hydroxy-3,2'-dimethyl-4-aminobiphenyl and N-hydroxy-4-aminobiphenyl (primarily substrates for OAT) were 82-84 in liver, 13-20 in small intestine and 3.8-5.3 in large intestine and for DNA binding of N-hydroxy-2-acetylamidofluorene (a substrate for AHAT), the ratio was 432 in liver, 32-161 in small intestine and 8.8-13.5 in large intestine. The data show also that NAT1 activity is uniformly distributed along the intestinal tract whereas NAT2 activity is highest in the small intestine. In addition, hepatic and intestinal OAT and AHAT but not NAT1 activities in the rabbit intestine are similarly distributed to activities for NAT2, suggesting that NAT2, OAT and AHAT activities are properties of a single protein in the rapid acetylator phenotype. Moreover, OAT and AHAT activities were much higher in tissues from the rapid than the slow phenotype. The data support the hypothesis that phenotype-dependent metabolic activation of N-OH heterocyclic or aromatic amines to reactive acetoxy metabolites may be involved in the etiology of colorectal cancer.

Tissue distribution of N‐acetyltransferase 1 and 2 catalyzing the N‐acetylation of 4‐aminobiphenyl and O‐acetylation of N‐hydroxy‐4‐aminobiphenyl in the congenic rapid and slow acetylator Syrian hamster

“…This is consistent with previous studies reporting a general decrease in NAT2 activity along the gastrointestinal tract in rabbits [21], Syrian hamsters [38], and humans [25]. Although SMZ N-acetyltransferase activity (NAT1) was highest in liver, it was detected in all tissues tested except for prostate and heart.…”

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

“…However, the relative expression of the arylamine NAT1 and NAT2 isozymes may differ in human colons. For example, recent studies in the rabbit have reported that NAT2 is primarily expressed in the upper intestinal tract (duodenum and jejunum) with little or none present in the large intestine (Ilett et al 1991;Reeves et al 1992). In contrast, NAT1 expression was uniformly high along the rabbit intestinal tract.…”

N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk

“…This hypothesis derives from studies in the rabbit model where N-acetyltransferase activities reflected the NAT2 genetic polymorphism in the liver and gut, but not in other tissue cytosols, suggesting either absence or a much smaller contribution of rabbit NAT2 in these other tissues (Hearse and Weber, 1973). Furthermore, a subsequent study reported that the rapid/slow NAT2 ratio for both sulfamethazine Nacetyltransferase and N-hydroxy-ABP O-acetyltransferase activities were much higher in rabbit liver than small and large intestine (Ilett et al, 1991). Thus, these studies in rabbit suggested that NAT2 genotype-dependent differences are expressed primarily in the liver and to a lesser extent in the gastrointestinal tract, and therefore suggest that NAT2 genotype-dependent differences in carcinogenesis following exposures to carcinogens primarily reflect NAT2 genotype-dependent hepatic versus extrahepatic metabolism of the carcinogen and/or its metabolites.…”