Fernandes C L, Dong J H, Roebuck B D, Chisari F V, Montali J A, Schmidt D E, Prochaska H J
Molecular Pharmacology and Therapeutics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Arch Biochem Biophys. 1996 Jul 1;331(1):104-16. doi: 10.1006/abbi.1996.0288.
Hepatic levels of GSH and Phase II detoxication enzymes were compared to biochemical and histological indices of hepatic damage in 4- to 76-week-old nontransgenic mice and their transgenic littermates that overexpress the hepatitis B virus large envelope protein. The mice were fed a low-sucrose AIN-76A diet ad libitum. Hepatic-specific activities of quinone reductase (QR) and glutathione S-transferase (GST) were increased 2- to 10-fold beginning at 12 weeks of age in transgenic mice and correlated with increases in serum alanine aminotransferase (ALT) (r = 0.84 and 0.59, respectively). Quantitative histological analysis demonstrated that apoptosis was the predominant feature in 4- to 12-week-old transgenic mice, whereas necrosis and inflammation predominated at later time points. Surprisingly, 3-fold elevations in ALT were observed beginning at 52 weeks of age in nontransgenic mice, and hepatic-specific activities of QR and GST were also modestly increased in elderly nontransgenic animals. In contrast to transgenic mice, apoptosis was not a prominent feature. The strongest histological correlates to ALT in 4- to 76-week-old nontransgenic mice were necrosis and inflammation (r > 0.96), which in turn may have been evoked by hepatic fat accumulation. Profiles of specific GST isoforms were quantitated chromatographically and identified by sequencing tryptic digests. The Ya1 subunit of alpha-class GST was markedly increased from undetectable levels in transgenic mice, while more modest increases were observed in nontransgenic mice more than 1 year old. Fivefold elevations of the Yb1 subunit, a constitutively expressed mu-class GST, were found in transgenic mice older than 4 weeks of age, while 2-fold increases were observed in nontransgenic animals that were more than 1 year old. These studies demonstrate that selected increases in Phase II detoxication enzymes are a stereotyped response to chronic hepatitis that is strikingly reminiscent of the treatment of mice with anticarcinogenic enzyme inducers.
在4至76周龄的非转基因小鼠及其过表达乙肝病毒大蛋白的转基因同窝小鼠中，比较了肝脏谷胱甘肽（GSH）水平和II相解毒酶与肝脏损伤的生化及组织学指标。小鼠自由采食低蔗糖AIN - 76A饮食。转基因小鼠从12周龄开始，醌还原酶（QR）和谷胱甘肽S - 转移酶（GST）的肝脏特异性活性增加了2至10倍，且与血清丙氨酸氨基转移酶（ALT）升高相关（r分别为0.84和0.59）。定量组织学分析表明，凋亡是4至12周龄转基因小鼠的主要特征，而坏死和炎症在后期更为突出。令人惊讶的是，非转基因小鼠从52周龄开始ALT升高了3倍，老年非转基因动物的肝脏QR和GST特异性活性也有适度增加。与转基因小鼠不同，凋亡不是突出特征。在4至76周龄的非转基因小鼠中，与ALT最强的组织学相关性是坏死和炎症（r>0.96），这反过来可能是由肝脏脂肪堆积引起的。通过色谱法定量特定GST同工型的谱图，并通过胰蛋白酶消化产物测序进行鉴定。α类GST的Ya1亚基在转基因小鼠中从不可检测水平显著增加，而在1岁以上的非转基因小鼠中增加幅度较小。在4周龄以上的转基因小鼠中，组成型表达的μ类GST的Yb1亚基升高了5倍，而在1岁以上的非转基因动物中升高了2倍。这些研究表明，II相解毒酶的特定增加是对慢性肝炎的一种典型反应，这与用抗癌酶诱导剂治疗小鼠的情况惊人地相似。
