Ilett K F, Reeves P T, Minchin R F, Kinnear B F, Watson H F, Kadlubar F F
Department of Pharmacology, University of Western Australia, Nedlands.
Carcinogenesis. 1991 Aug;12(8):1465-9. doi: 10.1093/carcin/12.8.1465.
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.
流行病学研究表明，结直肠肿瘤患者中快速乙酰化酶表型的比例显著高于对照组；肠道上皮细胞中饮食或环境胺生物活化的表型相关差异被认为是造成这种影响的一种机制。在本研究中，我们使用肝脏和肠道胞质溶胶来比较快速和慢速乙酰化酶兔中N - 乙酰转移酶（NAT1和NAT2）、O - 乙酰转移酶（OAT）和芳基异羟肟酸N,O - 酰基转移酶（AHAT）的分布。对氨基苯甲酸乙酰化（NAT1的选择性底物）的比率（快速/慢速）在肝脏中为6，在小肠中为1.7 - 2，在大肠中为1.3 - 1.5，而磺胺二甲嘧啶乙酰化（NAT2的选择性底物）的比率在肝脏中为150，在小肠中为16 - 22，在大肠中为1.8 - 2.5。N - 羟基 - 3,2'-二甲基 - 4 - 氨基联苯和N - 羟基 - 4 - 氨基联苯（主要是OAT的底物）与DNA结合的比率（快速/慢速）在肝脏中为82 - 84，在小肠中为13 - 20，在大肠中为3.8 - 5.3，对于N - 羟基 - 2 - 乙酰氨基芴（AHAT的底物）与DNA结合，该比率在肝脏中为432，在小肠中为32 - 161，在大肠中为8.8 - 13.5。数据还表明，NAT1活性沿肠道均匀分布，而NAT2活性在小肠中最高。此外，兔肠道中的肝脏和肠道OAT及AHAT活性（但不是NAT1活性）与NAT2活性的分布相似，这表明NAT2、OAT和AHAT活性是快速乙酰化酶表型中单一蛋白质的特性。而且，快速表型组织中的OAT和AHAT活性比慢速表型高得多。这些数据支持这样的假设，即N - OH杂环或芳香胺向反应性乙酰氧基代谢物的表型依赖性代谢活化可能参与了结直肠癌的病因学。
