The essential role of microsomal deacetylase activity in the metabolic activation, DNA-(deoxyguanosin-8-yl)-2-aminofluorene adduct formation and initiation of liver tumors by N-hydroxy-2-acetylaminofluorene in the livers of infant male B6C3F1 mice.
The essential role of microsomal deacetylase activity in the metabolic activation, DNA-(deoxyguanosin-8-yl)-2-aminofluorene adduct formation and initiation of liver tumors by N-hydroxy-2-acetylaminofluorene in the livers of infant male B6C3F1 mice.
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微粒体脱乙酰酶活性在雄性婴儿 B6C3F1 小鼠肝脏中代谢激活、DNA-(脱氧鸟苷-8-基)-2-氨基芴加合物形成以及 N-羟基-2-乙酰氨基芴引发肝肿瘤中的重要作用。
DOI：
10.1093/carcin/9.7.1295
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发表时间：
1988
期刊：
影响因子：
4.7
通讯作者：
Liem,A
中科院分区：
文献类型：
--
作者：
Lai,CC;Miller,EC;Miller,JA;Liem,A
脱乙酰作用ofN-hydroxy-2-acetylaminofluorene。（n -羟基- AAF） n -羟基-2-氨基芴（n -羟基- af）被认为是12日龄雄性b6c3f1小鼠肝脏DNA加合物形成和肝脏肿瘤发生的关键代谢步骤之一。在这项研究中，通过使用一种羧酸酯酶和氨基酶抑制剂（对硝基苯基）磷酸（BNPP），证明了这些小鼠体内n -羟基aaf的微粒体去乙酰化酶活性在肝癌发生起始中的重要性，这种抑制剂的体内毒性比对氧磷小得多。用10−3M的BNPP对12日龄雄性b6c3f1小鼠肝微粒体进行预孵育，使去乙酰化酶活性降低80%，而对氧磷在10−4M浓度下完全抑制去乙酰化酶活性。12日龄雄性b6c3f1小鼠在给予n-羟基- aaf前预处理4 × 75 μg剂量的BNPP/g体重，使肝脏cn -(dguoo -8-yl)- af加合物水平分别降至1.09和0.68 pmol/mg DNA，而给予0.06和0.03 μmol n-羟基- aaf一次处理的小鼠分别为2.87和1.64 pmol/mg DNA。然而，BNPP预处理不影响这些剂量的N-羟基aaf形成的乙酰化DNA加合物N-(dGuo-8-yl)- aaf和3-(dGuo-N2-yl)- aaf的水平。BNPP预处理也能抑制n-羟基aaf对肝脏肿瘤的启动作用。因此，对于单剂量0.12、0.06和0.03 μmol n -羟基- aaf /g体重的小鼠，BNPP预处理10个月时肝脏肿瘤的多样性分别降低至5.6、1.0和0.3，而未预处理的多样性分别为11.8、4.8和1.7。另一方面，BNPP预处理对肝脏DNA-N-dGuo-8-yl -AF加合物的水平和相同剂量n -羟基-AF诱导的肝脏肿瘤多样性没有显著的抑制作用。综上所述，n-羟基- aaf的脱乙酰化对n-羟基- af的代谢激活、DNA-N-(dGuo-8-yl)- af加合物的形成和幼年雄性b6c3f1小鼠肝脏肿瘤的发生至关重要。
Deacetylation ofN-hydroxy-2-acetylaminofluorene. (N-hydroxy- AAF) toN-hydroxy-2-aminofluorene (N-hydroxy-AF) has been proposed as one of the critical metabolic steps in the formation of hepatic DNA adducts and the initiation of liver tumors in 12-day-old male B6C3F1mice. In this study, the importance of the microsomal deacetylase activity forN-hydroxy-AAF in the initiation of hepatocarcinogenesis in these mice was demonstrated by using a carboxylesterase and amidase inhibitor, bis(p-nitrophenyl)phosphate (BNPP), that is much less toxic in vivo than is paraoxon. Pre-incubation of liver microsomes from 12-day-old male B6C3F1mice with 10−3M BNPP reduced the deacetylase activity by 80% while paraoxon inhibited the deacetylase activity completely at a concentration of 10−4M. Pretreatment of 12-day-old male B6C3F1mice with 4 × 75 μg doses of BNPP/g body weight before the administration ofn-hydroxy-AAF reduced the hepaticN-(dGuo-8-yl)-AF adduct levels to 1.09 and 0.68 pmol/mg DNA compared with 2.87 and 1.64 pmol/mg DNA for mice treated once with 0.06 or 0.03 μmol ofN-hydroxy-AAF/g body weight respectively. However, BNPP pretreatments did not affect the levels of the acetylated DNA adducts,N-(dGuo-8-yl)-AAF and 3-(dGuo-N2-yl)-AAF, formed by these doses ofN-hydroxy-AAF. The initiation of liver tumors byn-hydroxy-AAF was also inhibited by BNPP pretreatment. Thus, for mice that received single doses of 0.12, 0.06 and 0.03 μmol ofN-hydroxy-AAF/g body weight, the multiplicities of liver tumors at 10 months were reduced by BNPP pretreatments to 5.6, 1.0 and 0.3 compared with multiplicities of 11.8, 4.8 and 1.7 without pretreatment respectively. On the other hand, BNPP pretreatments had no significant inhibitory effects on the levels of the hepatic DNA-N-dGuo-8-yl)-AF adduct or on the liver tumor multiplicities induced by comparable doses ofN-hydroxy-AF. It is concluded that deacetylation ofn-hydroxy-AAF toN-hydroxy-AF is essential for the metabolic activation, DNA-N-(dGuo-8-yl)-AF adduct formation and liver tumor initiation in infant male B6C3F1mice byN-hydroxy-AAF.