Metabolism and activation of the pancreatic carcinogen N-nitrosobis(2-oxopropyl)amine by isolated hepatocytes and pancreatic cells of the Syrian hamster.
Metabolism and activation of the pancreatic carcinogen N-nitrosobis(2-oxopropyl)amine by isolated hepatocytes and pancreatic cells of the Syrian hamster.
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叙利亚仓鼠分离的肝细胞和胰腺细胞对胰腺致癌物 N-亚硝基双（2-氧代丙基）胺的代谢和激活。
DOI：
10.1093/carcin/11.4.625
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发表时间：
1990
期刊：
影响因子：
4.7
通讯作者：
Kokkinakis,DM
中科院分区：
文献类型：
--
作者：
Mangino,MM;Scarpelli,DG;Kokkinakis,DM
采用叙利亚仓鼠原代肝细胞、腺泡和管细胞研究了胰腺癌致癌物n -亚硝基双（2-氧丙基）胺（BOP）的代谢。通过检测BOP转化为co2共价结合的代谢物和含有亚硝胺α-碳的可溶性产物，证实了BOP的代谢激活作用。当浓度低于0.2 mM时，BOP在60分钟内被肝细胞完全激活。在高底物浓度（1 mM）或高细胞密度（5 × 106个细胞/ml）下，BOP -n -亚硝基双（2-羟丙基）（2-氧丙基）胺和n -亚硝基双（2-羟丙基）胺的减少对代谢谱有显著影响。采用有利于BOP代谢激活的条件比较肝细胞和胰腺细胞的代谢。在此条件下，肝细胞与腺泡细胞形成的激活产物之比为14.5:1；共价结合代谢物的相应比例为19.1。从激活产物的产量来看，肝细胞激活BOP的速度是导管细胞的106倍，从细胞大分子标记来看，肝细胞激活BOP的速度是导管细胞的152倍。腺泡细胞表现出比导管细胞更高的代谢激活能力。腺泡细胞与导管细胞的激活产物产量之比为4.3:1；共价结合的对应比值为5.8:1。与肝细胞相比，胰腺细胞对BOP的激活能力相对较低，这与在体内给予BOP的仓鼠相比，胰腺的DNA结合水平较低是一致的。肝细胞与腺泡细胞中BOP的总共价结合比率高于肝细胞与胰细胞的总共价结合比率，这一观察结果与BOP衍生的烷基化剂在其他器官形成后到达胰腺的假设一致。肝脏将是这种烷基化剂的主要来源。
The metabolism of the pancreatic carcinogenN-nitrosobis(2-oxopropyl)amine (BOP) was studied using primary hepatacytes and acinar and duct cells isolated from Syrian hamsters. Metabolic activation of BOP was verified by detecting its converison to CO2covalently bound metabolites and soluble products containing the α-carbon of the nitrosamine. At concentrations below 0.2 mM, BOP was completely activated by hepatocytes within 60 min. At high substrate concentration (1 mM) or high cell density (5 × 106cells/ml), reduction of BOP toN-nitrosobis(2-hydroxypropyl) (2-oxopropyl)amine andN-nitrosobis(2-hydroxypropyl)amine contributed significantly to the metabolic profile. The conditions which favored metabolic activation of BOP were used to compare metabolism by hepatocytes and pancreatic cells. Under shuch conditions, the ratio of activation products formed by hepatocytes versus formed by acinar cells was 14.5:1; the corresponding ratio for covalently bound metabolites was 19:l. Hepatacytes activated BOP 106 times more rapidly than duct cells as determined from yields of activation products or 152 times more rapidly as determined from labeling of cellular macromolecules. Acinar cells showed a higher capacity for metabolic activation than duct cells. The ratio for the yield of activation products from acinar versus duct cells was 4.3:l; the corresponding ratio for covalent binding was 5.8:l. The relatively low capacity of pancreatic cells for activation of BOP compared to hepatocytes is in agreement with the low levels of DNA binding in the pancreas compared to other organs after administration of BOP to the hamsterin vivo. The observation that the ratio for total covalent binding of BOP in hepatacytes versus acinar cells was higher than that seen previously for the liver versus the pancreasin vivois consistent with the hypothesis that alkylating agents derived from BOP reach the pancreas after formation in other organs. The liver would be the prime source for such alkylating agents.