The effect of inducers of mixed-function oxidases on hepatic microsome-mediated aflatoxin B1 transformation in C3H/10T1/2 cells.
The effect of inducers of mixed-function oxidases on hepatic microsome-mediated aflatoxin B1 transformation in C3H/10T1/2 cells.
复制标题
混合功能氧化酶诱导剂对 C3H/10T1/2 细胞中肝微粒体介导的黄曲霉毒素 B1 转化的影响。
DOI：
10.1016/0041-008x(89)90230-5
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发表时间：
1989
影响因子：
3.8
通讯作者：
Gurtoo,HL
中科院分区：
文献类型：
--
作者：
Faletto,MB;Gurtoo,HL
黄曲霉毒素B1（AFB 1）是一种强肝毒素和致癌物，通过与肝脏混合功能氧化酶系统相关的不同形式的细胞色素P450代谢。本研究以C3 H 10 T1 2（10 T1 2）细胞为研究对象，在大鼠肝微粒体存在下，用黄曲霉毒素B1处理C3 H 10 T1 2（10 T1 2）细胞，观察特异性细胞色素P450的诱导对黄曲霉毒素B1介导的毒性和转化的影响。相对于未诱导的微粒体，苯巴比妥（PB）处理诱导AFB 1-DNA结合（基本上代表AFB 1 - 8，9-氧化物与DNA结合的形成）3.2倍，而Aroclor 1254、3-甲基胆蒽（3-MC）或5，6-苯并吡喃酮（β-NF）预处理优先诱导黄曲霉毒素M1（AFM 1）形成2- 5倍。将10个T 1 2细胞暴露于4 μm AFB 1和未诱导、PB-、Aroclor 1254-、3-MC-或β-NF-处理大鼠肝微粒体的多重处理方案;产生的累积毒性分别约为对照（无微粒体）值的90、95、70、60和40%。增强的AFB 1转化反应与不同处理中观察到的毒性增加相关，未诱导或PB诱导的微粒体产生约4个病灶/培养皿，而Aroclor 1254、3-MC或β-NF诱导的微粒体处理仅产生1 - 2个病灶/培养皿。这些结果表明，在10 T1 - 2系统中，当与适当的肝微粒体激活系统结合使用重复孵育时，AFB 1是一种完全的致癌物。这些数据还与AFB 1 -4-羟化酶的诱导与AFB 1介导的毒性和10 T12细胞转化的降低相关，并支持AFB 1在肝脏中的I相代谢转化为AFM 1本身是一种有效的解毒途径的假设。
The potent hepatotoxin and hepatocarcinogen aflatoxin B1(AFB1) is metabolized by different forms of cytochrome P450 associated with the hepatic mixed-function oxidase system. C3H 10T 1 2 (10 T 1 2 ) cells, which have limited inherent capacity to metabolize AFB1, were treated with AFB1in the presence of hepatic microsomes isolated from chemically treated rats to investigate the effects of the induction of specific cytochromes P450 on AFB1-mediated toxicity and transformation. Relative to uninduced microsomes, phenobarbital (PB) treatment induced AFB1-DNA binding (essentially representing the formation of AFB1-8,9-oxide bound to DNA) 3.2-fold, while pretreatment with Aroclor 1254, 3-methylcholanthrene (3-MC), or 5,6-benzoflavone (β-NF) preferentially induced aflatoxin M1(AFM1) formation from 2- to 5-fold. 10 T 1 2 cells were exposed to a multiple treatment regimen with 4 μm AFB1and hepatic microsomes from uninduced, PB-, Aroclor 1254-, 3-MC-, or β-NF-treated rats; respective cumulative toxicities of approximately 90, 95, 70, 60, and 40% control (no microsomes) values resulted. An enhanced AFB1transformation response correlated with the increasing toxicities observed for the different treatments, with uninduced or PB-induced microsomes yielding approximately four foci/dish, while treatments with Aroclor 1254-, 3-MC-, or β-NF-induced microsomes resulted in only one to two foci/dish. These results demonstrate that AFB1is a complete carcinogen in the 10 T 1 2 system when repetitive incubations are used in conjunction with an appropriate hepatic microsomal activation system. These data also correlate the induction of AFB1-4-hydroxylase with a decrease in AFB1-mediated toxicity and transformation of 10 T 1 2 cells, and support the hypothesis that the Phase I metabolic conversion of AFB1to AFM1in the liver represents an effective detoxication pathway per se.