Feng Y, Fretland A J, Rustan T D, Jiang W, Becker W K, Hein D W
Department of Pharmacology and Toxicology, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202, USA.
Toxicol Appl Pharmacol. 1997 Nov;147(1):56-62. doi: 10.1006/taap.1997.8259.
Humans and other mammals such as rats exhibit a genetic polymorphism in acetyltransferase (NAT2) capacity, yielding rapid and slow acetylator phenotypes. The rapid acetylator phenotype has been associated with increased incidence of human colorectal cancer in some, but not all, epidemiological studies. In order to investigate this possible association, a rapid (F-344) and slow (WKY) acetylator inbred rat model was utilized to investigate the role of the acetylator genotype (NAT2) in the formation of aberrant crypt foci (ACF) following administration of colon carcinogens. Age-matched (retired breeder) female rapid and slow acetylator inbred rats received two weekly injections (50 or 100 mg/kg, sc) of 3,2'-dimethyl-4-aminobiphenyl (DMABP) or a single 50 mg/kg, sc, injection of 1,2-dimethyl-hydrazine (DMH). The rats were euthanized at 10 weeks and ACF were evaluated in the cecum, ascending, transverse, and descending colon, and rectum. ACF were observed in the colon and rectum, but not the cecum of rapid and slow acetylator inbred rats administered DMABP or DMH. ACF were more concentrated in the descending colon. ACF frequencies were significantly higher in colons of rapid than slow acetylator inbred rats administered DMABP, a colon carcinogen which is activated via O-acetylation catalyzed by polymorphic acetyltransferase (NAT2). At 50 mg/kg, ACF frequency in the distal colon was 2.29 +/- 0.57 in rapid acetylators versus 0.38 +/- 0.18 in slow acetylators. At 100 mg/kg, ACF frequency was 4.11 +/- 1.06 in rapid versus 1.57 +/- 0.48 in slow acetylators. ACF frequency did not differ significantly between rapid and slow acetylator inbred rats administered DMH, a colon carcinogen which is not metabolized by polymorphic acetyltransferase. The two inbred rat strains did not differ in hepatic microsomal phenacetin deethylase activity, which is a marker for CYP1A2 activity important for the activation of aromatic amines. These results support the hypothesis that rapid acetylator (NAT2) genotype is a risk factor in aromatic amine-induced colon carcinogenesis.
人类和其他哺乳动物（如大鼠）在乙酰转移酶（NAT2）能力方面表现出基因多态性，产生快速乙酰化和缓慢乙酰化表型。在一些但并非所有的流行病学研究中，快速乙酰化表型与人类结直肠癌发病率增加有关。为了研究这种可能的关联，利用快速（F - 344）和缓慢（WKY）乙酰化近交系大鼠模型来研究乙酰化基因型（NAT2）在给予结肠致癌物后异常隐窝灶（ACF）形成中的作用。年龄匹配（退休繁殖鼠）的快速和缓慢乙酰化近交系雌性大鼠每周皮下注射两次（50或100 mg/kg）3,2'-二甲基-4-氨基联苯（DMABP），或单次皮下注射50 mg/kg 1,2-二甲基肼（DMH）。在第10周对大鼠实施安乐死，并在盲肠、升结肠、横结肠、降结肠和直肠中评估ACF。在给予DMABP或DMH的快速和缓慢乙酰化近交系大鼠的结肠和直肠中观察到了ACF，但在盲肠中未观察到。ACF在降结肠中更为集中。在给予通过多态性乙酰转移酶（NAT2）催化的O - 乙酰化而活化的结肠致癌物DMABP的情况下，快速乙酰化近交系大鼠结肠中的ACF频率显著高于缓慢乙酰化近交系大鼠。在50 mg/kg剂量下，快速乙酰化大鼠远端结肠中的ACF频率为2.29±0.57，而缓慢乙酰化大鼠为0.38±0.18。在100 mg/kg剂量下，快速乙酰化大鼠的ACF频率为4.11±1.06，缓慢乙酰化大鼠为1.57±0.48。在给予不由多态性乙酰转移酶代谢的结肠致癌物DMH的快速和缓慢乙酰化近交系大鼠之间，ACF频率没有显著差异。这两种近交系大鼠在肝微粒体非那西丁脱乙基酶活性方面没有差异，该酶活性是对芳香胺活化很重要的CYP1A2活性的标志物。这些结果支持了快速乙酰化（NAT2）基因型是芳香胺诱导的结肠癌发生中的一个危险因素这一假设。
