Flammang T J, Yamazoe Y, Guengerich F P, Kadlubar F F
National Center for Toxicological Research, Jefferson, AR 72079.
Carcinogenesis. 1987 Dec;8(12):1967-70. doi: 10.1093/carcin/8.12.1967.
A genetic polymorphism in the enzymatic N-acetylation of sulfamethazine and other drugs in humans is well known and has been related to differential susceptibility to drug toxicities. Carcinogenic aromatic amines such as 2-aminofluorene also undergo N-acetylation, and phenotypic slow acetylator individuals have been suggested to be at increased risk to arylamine-induced urinary bladder cancer. However, acetyltransferases have also been shown to catalyze a final metabolic activation step in the conversion of both hydroxamic acid (e.g. N-hydroxy-N-acetyl-2-aminofluorene N,O-acyltransferase) and N-hydroxy-arylamine (e.g. N-hydroxy-2-aminofluorene O-acetyltransferase) metabolites to DNA-bound adducts. In this regard, rapid acetylators have recently been reported to be at higher risk for colorectal cancer. In this study, we examined the enzymatic activity of 35 human liver cytosol samples (obtained surgically from organ donors) for sulfamethazine and 2-aminofluorene N-acetyltransferase activities, N-hydroxy-N-acetyl-2-aminofluorene N,O-acyltransferase activity, and the acetyl coenzyme A (CoA)-dependent O-acetylation of N-hydroxy-2-aminofluorene to form DNA-bound products. The results with sulfamethazine indicated that about two-thirds of the human liver samples were of the slow acetylator phenotype; the same individuals also exhibited levels of 2-aminofluorene N-acetylation that were consistent with their respective sulfamethazine-N-acetylation activity. N-Hydroxy-N-acetyl-2-aminofluorene N,O-acyltransferase activity was not detected. However, the acetyl CoA-dependent activation of N-hydroxy-2-aminofluorene was observed for nearly all of the samples and was consistently higher in the fast acetylator group. These data support the hypothesis that phenotypic rapid acetylator individuals are likely to be at higher risk to aromatic amine-induced cancers in those tissues containing appreciable levels of N-hydroxy arylamine O-acetyltransferase.
人类中磺胺二甲嘧啶及其他药物的酶促N - 乙酰化存在遗传多态性，这是众所周知的，并且与药物毒性的易感性差异有关。致癌芳香胺如2 - 氨基芴也会发生N - 乙酰化，有人提出表型为慢乙酰化者患芳胺诱导的膀胱癌的风险增加。然而，乙酰转移酶也已被证明可催化异羟肟酸（如N - 羟基 - N - 乙酰 - 2 - 氨基芴N，O - 酰基转移酶）和N - 羟基芳胺（如N - 羟基 - 2 - 氨基芴O - 乙酰转移酶）代谢产物转化为与DNA结合的加合物的最终代谢活化步骤。在这方面，最近有报道称快速乙酰化者患结直肠癌的风险更高。在本研究中，我们检测了35份人肝脏胞质溶胶样品（通过手术从器官供体获得）中磺胺二甲嘧啶和2 - 氨基芴N - 乙酰转移酶活性、N - 羟基 - N - 乙酰 - 2 - 氨基芴N，O - 酰基转移酶活性，以及N - 羟基 - 2 - 氨基芴的乙酰辅酶A（CoA）依赖性O - 乙酰化以形成与DNA结合产物的活性。磺胺二甲嘧啶的检测结果表明，约三分之二的人肝脏样品为慢乙酰化者表型；同样这些个体的2 - 氨基芴N - 乙酰化水平与各自的磺胺二甲嘧啶 - N - 乙酰化活性一致。未检测到N - 羟基 - N - 乙酰 - 2 - 氨基芴N，O - 酰基转移酶活性。然而，几乎所有样品都观察到了N - 羟基 - 2 - 氨基芴的乙酰CoA依赖性活化，并且在快速乙酰化者组中始终较高。这些数据支持了这样的假设，即在含有相当水平的N - 羟基芳胺O - 乙酰转移酶的组织中，表型为快速乙酰化者个体患芳香胺诱导癌症的风险可能更高。
