In vitro metabolism of N”-Nitrosonornicotine catalyzed by cytochrome P450 2A13 and its inhibition by nicotine,N”-Nitrosoanatabine and N”-Nitrosoanabasine
N”-Nitrosonornicotine(NNN)is considered to be one of the most carcinogenic compounds of the four conventionally measured tobacco-specific N-nitrosamines(TSNAs).In order to evaluate the significance of metabolic activation for the carcinogenic potential of NNN,its catalysis by different phase I enzymes and its interaction with nicotine and nicotine-derived TSNAs need to be investigated.Using an in vitro model system,NNN was found to interact with various cytochrome P450 enzymes,predominantly CYP2A13.Mass-spectrometric analysis confirmed the presence of various predicted NNN metabolites,including 4-hydroxy-1-(3-pyridyl)-1-butanone(HPB)and 4-hydroxy-4-(3-pyridyl)-butyric acid(hydroxy acid)but little amount of 4-oxo-4-(3-pyridyl)butanal(OPB),which was somewhat different from in vitro NNK metabolism.Addition of nicotine,N”-Nitrosoanatabine(NAT),N”-Nitrosoanabasine(NAB)resulted in a competitive inhibition for NNN metabolism.The inhibition constant Ki value was calculated as 0.98 μM(nicotine),1.37 μM(NAT),0.71 μM(NAB)for HPB formation,1.35 μM(nicotine),1.35 μM(NAT),1.01 μM(NAB)for hydroxy acid formation and 8.40 μM(nicotine),3.40 μM(NAT),3.04 μM(NAB)for OPB formation,respectively.These results implied that CYP2A13 is the most efficient enzyme to metabolize NNN in vitro and structurally similar tobacco constitutes including nicotine,NAT and NAB influence the metabolic activation of NNN,which may further interfere in its carcinogenicity.
NNN Cytochrome P450 Metabolism Inhibition
Xingyu Liu Jie Zhang Limeng Wang Bicheng Yang Chen Zhang Wei Liu Jun Zhou
Shanghai Tobacco Group Corporation of CNTC,99 Wansheng South Street,Tongzhou District,Beijing 101121 Dalian Institute of Chemical Physics,University of Chinese Academy of Sciences,457 Zhongshan Road,Da Jiangxi Provincial Maternal And Child Health Hospital,318 Bayi Road,Nanchang 330006,Jiangxi,China
国内会议
北京
英文
1-22
2017-11-01（万方平台首次上网日期，不代表论文的发表时间）