Fretland Adrian J, Devanaboyina Uday S, Doll Mark A, Zhao Shuang, Xiao Gong H, Hein David W
Department of Pharmacology and Toxicology and James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky 40292, USA.
Toxicol Sci. 2003 Aug;74(2):253-9. doi: 10.1093/toxsci/kfg133. Epub 2003 May 28.
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic amine carcinogen prevalent in the human diet. To exert its mutagenic and carcinogenic effects, PhIP undergoes bioactivation to N-hydroxy-PhIP followed by O-esterification via cytosolic acetyltransferases or sulfotransferases to form DNA adducts. We investigated the role of cytosolic acetyltransferases and sulfotransferases and the role of the N-acetyltransferase 2 genetic polymorphism on PhIP DNA-adduct levels in a congenic Syrian hamster model. DNA adduct levels were detected in all hepatic and extrahepatic tissues tested following administration of PhIP (4x100 mg/kg) or N-hydroxy-PhIP (1x50 mg/kg), with the highest levels in pancreas. DNA-adduct levels were higher in the gastrointestinal tract of rapid and slow acetylator hamsters administered N-hydroxy-PhIP. N-hydroxy-PhIP O-acetyltransferase and O-sulfotransferase activities were detected in most hepatic and extrahepatic cytosols derived from rapid and slow acetylator congenic hamsters. N-hydroxy-PhIP O-acetyltransferase activity was significantly higher (p<0.05) in liver, small intestine, and esophagus in rapid than in slow acetylator congenic hamsters. N-hydroxy-PhIP O-acetyltransferase activities correlated significantly with N-acetyltransferase 2 activities across tissues in rapid (r=0.83; p=0.0004) but not in slow (r=0.46; p=0.1142) acetylator congenic hamsters, suggesting catalysis primarily by NAT2 in rapid acetylators but NAT1 in slow acetylators. N-hydroxy-PhIP O-sulfotransferase activities did not vary with acetylator genotype. DNA-adduct levels following administration of PhIP or N-hydroxy-PhIP did not correlate with either N-hydroxy-PhIP O-acetyltransferase or O-sulfotransferase catalytic activities.
2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶（PhIP）是一种在人类饮食中普遍存在的杂环胺致癌物。为发挥其诱变和致癌作用，PhIP先经生物活化生成N-羟基-PhIP，然后通过胞质乙酰转移酶或磺基转移酶进行O-酯化反应，形成DNA加合物。我们在同基因叙利亚仓鼠模型中研究了胞质乙酰转移酶和磺基转移酶的作用以及N-乙酰转移酶2基因多态性对PhIP DNA加合物水平的影响。在给予PhIP（4×100 mg/kg）或N-羟基-PhIP（1×50 mg/kg）后，检测了所有受试肝组织和肝外组织中的DNA加合物水平，其中胰腺中的水平最高。给予N-羟基-PhIP后，快速和慢速乙酰化仓鼠胃肠道中的DNA加合物水平更高。在快速和慢速乙酰化同基因仓鼠的大多数肝组织和肝外细胞溶质中检测到N-羟基-PhIP O-乙酰转移酶和O-磺基转移酶活性。快速乙酰化同基因仓鼠肝脏、小肠和食管中的N-羟基-PhIP O-乙酰转移酶活性显著高于慢速乙酰化同基因仓鼠（p<0.05）。在快速乙酰化同基因仓鼠中，各组织间N-羟基-PhIP O-乙酰转移酶活性与N-乙酰转移酶2活性显著相关（r=0.83；p=0.0004），而在慢速乙酰化同基因仓鼠中则无显著相关性（r=0.46；p=0.1142），这表明在快速乙酰化仓鼠中主要由NAT2催化，而在慢速乙酰化仓鼠中主要由NAT1催化。N-羟基-PhIP O-磺基转移酶活性不随乙酰化基因型而变化。给予PhIP或N-羟基-PhIP后的DNA加合物水平与N-羟基-PhIP O-乙酰转移酶或O-磺基转移酶催化活性均无相关性。
