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首页> 外文期刊>Archives of Toxicology >Toxicokinetics of acrylamide in primary rat hepatocytes: Coupling to glutathione is faster than conversion to glycidamide
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Toxicokinetics of acrylamide in primary rat hepatocytes: Coupling to glutathione is faster than conversion to glycidamide

机译：丙烯酰胺在原代大鼠肝细胞中的毒代动力学：与谷胱甘肽的偶联比向缩水甘油酰胺的转化更快

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Acrylamide (AA), classified as class 2A carcinogen (probably carcinogenic to humans) by the International Agency for Research on Cancer (IARC), is formed during heating of food from reducing carbohydrates and asparagine by Maillard reaction chemistry. After dietary uptake, AA is in part metabolically converted into the proximate genotoxic phase I metabolite glycidamide (GA). GA reacts with nucleophilic base positions in DNA, primarily forming N7-(2-carbamoyl-2- hydroxyethyl)guanine (N7-GA-Gua) adducts. In a competing phase II biotransformation pathway AA, as well as its phase I metabolite GA, is coupled to glutathione (GSH). The GSH coupling products are further biotransformed and excreted via urine as mercapturic acids (MA), N-acetyl-S-(2-carbamoylethyl) cysteine (AAMA), and N-acetyl-S-(2-hydroxy-2-carbamoylethyl)cysteine (GAMA). In the present study, hepatic biotransformation pathways and DNA adduct formation were studied in primary rat hepatocytes, incubated with AA (0.2-2,000 μM) for up to 24 h. Contents of AA-GSH, GA, AAMA, and GAMA were measured in the cell culture medium after solid phase extraction (SPE). N7-GA-Gua adducts in DNA of hepatocytes were determined by HPLC-ESI-MS/MS after lysis of the cells and neutral thermal hydrolysis. Formation of AA-GSH was linear with AA concentration and incubation time and became detectable already at 0.2 μM (4 h). In contrast to AA, GA was not detected before 16 h incubation at 10-fold higher AA concentration (2 μM). In summary, the rate of AA-GSH formation was found to be about 1.5-3 times higher than that of GA formation. N7-GA-Gua adducts were found only at the highest AA concentration tested (2,000 μM).
机译：国际癌症研究机构（IARC）将丙烯酰胺（AA）归类为2A类致癌物（可能对人类致癌），是在通过美拉德反应化学方法从还原碳水化合物和天冬酰胺的食物加热过程中形成的。饮食摄入后，AA会部分代谢转化为遗传毒性I期代谢物缩水甘油酰胺（GA）。 GA与DNA中的亲核碱基位置反应，主要形成N7-（2-氨基甲酰基-2-羟乙基）鸟嘌呤（N7-GA-Gua）加合物。在竞争性的II期生物转化途径中，AA及其I期代谢产物GA与谷胱甘肽（GSH）偶联。 GSH偶联产物通过硫脲酸（MA），N-乙酰基-S-（2-氨基甲酰基乙基）半胱氨酸（AAMA）和N-乙酰基-S-（2-羟基-2-氨基甲酰基乙基）进一步生物转化并通过尿液排泄。半胱氨酸（GAMA）。在本研究中，研究了原代大鼠肝细胞的肝脏生物转化途径和DNA加合物的形成，并与AA（0.2-2,000μM）孵育长达24小时。在固相萃取（SPE）后，在细胞培养基中测量AA-GSH，GA，AAMA和GAMA的含量。细胞裂解和中性热水解后，通过HPLC-ESI-MS / MS测定肝细胞DNA中的N7-GA-Gua加合物。 AA-GSH的形成与AA浓度和孵育时间呈线性关系，并且在0.2μM（4 h）时就已经可以检测到。与AA相比，在以高10倍的AA浓度（2μM）孵育16小时之前未检测到GA。总之，发现AA-GSH的形成速率比GA的形成速率高约1.5-3倍。仅在测试的最高AA浓度（2,000μM）下发现N7-GA-Gua加合物。

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