Codominant Expression of N-Acetylation and O-Acetylation Activities Catalyzed by N-Acetyltransferase 2 in Human Hepatocytes

被引:34
作者
Doll, Mark A. [1 ,2 ]
Zang, Yu [1 ,2 ]
Moeller, Timothy [3 ]
Hein, David W. [1 ,2 ]
机构
[1] Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA
[2] Univ Louisville, Sch Med, James Graham Brown Canc Ctr, Louisville, KY 40292 USA
[3] Celsis In Vitro Technol Inc, Baltimore, MD USA
基金
美国国家卫生研究院;
关键词
SINGLE-NUCLEOTIDE POLYMORPHISM; CARCINOGEN-DNA ADDUCTS; HUMAN LIVER; ARYLAMINE CARCINOGENS; METABOLIC-ACTIVATION; CHINESE POPULATION; URINARY-BLADDER; GENETIC-CONTROL; SYRIAN-HAMSTER; CANCER-RISK;
D O I
10.1124/jpet.110.168567
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Human populations exhibit genetic polymorphism in N-acetylation capacity, catalyzed by N-acetyltransferase 2 (NAT2). We investigated the relationship between NAT2 acetylator genotype and phenotype in cryopreserved human hepatocytes. NAT2 genotypes determined in 256 human samples were assigned as rapid (two rapid alleles), intermediate (one rapid and one slow allele), or slow (two slow alleles) acetylator phenotypes based on functional characterization of the NAT2 alleles reported previously in recombinant expression systems. A robust and significant relationship was observed between deduced NAT2 phenotype (rapid, intermediate, or slow) and Nacetyltransferase activity toward sulfamethazine (p similar to 0.0001) and 4-aminobiphenyl (p < 0.0001) and for O-acetyltransferasecatalyzed metabolic activation of N-hydroxy-4-aminobiphenyl (p < 0.0001), N-hydroxy-2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (p < 0.01), and N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (p < 0.0001). NAT2-specific protein levels also significantly associated with the rapid, intermediate, and slow NAT2 acetylator phenotypes (p < 0.0001). As a negative control, p-aminobenzoic acid (an N-acetyltransferase 1-selective substrate) N-acetyltransferase activities from the same samples did not correlate with the three NAT2 acetylator phenotypes (p < 0.05). These results clearly document codominant expression of human NAT2 alleles resulting in rapid, intermediate, and slow acetylator phenotypes. The three phenotypes reflect levels of NAT2 protein catalyzing both N-and O-acetylation. Our results suggest a significant role of NAT2 acetylation polymorphism in arylamine-induced cancers and are consistent with differential cancer risk and/or drug efficacy/toxicity in intermediate compared with rapid or slow NAT2 acetylator phenotypes.
引用
收藏
页码:540 / 544
页数:5
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