Kokkinakis D M, Reddy M K, Norgle J R, Baskaran K
Department of Pharmacology, Northwestern University Medical School, Chicago, IL.
Carcinogenesis. 1993 Aug;14(8):1705-9. doi: 10.1093/carcin/14.8.1705.
Metabolism of 14C labeled N-nitrosobis(2-oxopropyl)amine (BOP), N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) and N-nitrosobis(2-hydroxypropyl)amine (BHP) by pancreatic duct cells in culture involves the following two pathways: reduction or oxidation reactions at the beta-carbon which result in the inter-conversion of these nitrosamines and activation reactions which result in the decomposition of the nitrosamine, the evolution of 14CO2 and the labeling of macromolecules. Reduction of BOP to HPOP seems to contribute significantly to the metabolism of the former nitrosamine by pancreatic duct cells, however, redox reactions at the beta-carbon of HPOP or BHP are not extensive. In terms of DNA damage, all three nitrosamines yield methyl and hydroxypropyl adducts. As expected, HPOP and BHP yield higher levels of O6-hydroxypropylguanine than BOP, while the latter yields higher levels of O6-methylguanine. There is no correlation between the ability of these nitrosamines to alkylate duct cell DNA in vitro and their carcinogenic potency in vivo. Concentrations of DNA adducts induced by pancreas specific nitrosamines (PSNs) in cultured duct cells at concentrations comparable to those found in the pancreatic juice of animals treated with BOP, are almost an order of magnitude lower than those induced in the pancreas of such animals. Discrepancies between in vitro and in vivo formation of active metabolites and DNA adducts may be attributed to the decline of the cells' ability to activate PSNs during culturing. In the same vein, the ductal cell may not be the main source of active metabolites targeting its DNA in the animal model.
培养的胰腺导管细胞对14C标记的N-亚硝基双（2-氧代丙基）胺（BOP）、N-亚硝基（2-羟丙基）（2-氧代丙基）胺（HPOP）和N-亚硝基双（2-羟丙基）胺（BHP）的代谢涉及以下两条途径：β-碳处的还原或氧化反应，导致这些亚硝胺的相互转化；以及激活反应，导致亚硝胺分解、14CO2释放和大分子标记。BOP还原为HPOP似乎对胰腺导管细胞对前一种亚硝胺的代谢有显著贡献，然而，HPOP或BHP的β-碳处的氧化还原反应并不广泛。就DNA损伤而言，所有三种亚硝胺都会产生甲基和羟丙基加合物。正如预期的那样，HPOP和BHP产生的O6-羟丙基鸟嘌呤水平高于BOP，而后者产生的O6-甲基鸟嘌呤水平更高。这些亚硝胺在体外使导管细胞DNA烷基化的能力与其在体内的致癌潜力之间没有相关性。胰腺特异性亚硝胺（PSNs）在培养的导管细胞中诱导的DNA加合物浓度，与用BOP处理的动物胰液中发现的浓度相当，但几乎比这些动物胰腺中诱导的浓度低一个数量级。体外和体内活性代谢物及DNA加合物形成之间的差异，可能归因于培养过程中细胞激活PSNs能力的下降。同样，在动物模型中，导管细胞可能不是靶向其DNA的活性代谢物的主要来源。
