Carretero M V, Latasa M U, Garcia-Trevijano E R, Corrales F J, Wagner C, Mato J M, Avila M A
División de Hepatología y Terapia Génica, Facultad de Medicina (Ed. Los Castaños), Universidad de Navarra, C/ Irunlarrea 1, 31008 Pamplona, Spain.
Biochem Pharmacol. 2001 May 1;61(9):1119-28. doi: 10.1016/s0006-2952(01)00590-1.
Methionine adenosyltransferase (MAT) is an essential enzyme that catalyzes the synthesis of S-adenosylmethionine (AdoMet), the most important biological methyl donor. Liver MAT I/III is the product of the MAT1A gene. Hepatic MAT I/III activity and MAT1A expression are compromised under pathological conditions such as alcoholic liver disease and hepatic cirrhosis, and this gene is silenced upon neoplastic transformation of the liver. In the present work, we evaluated whether MAT1A expression could be targeted by the polycyclic arylhydrocarbon (PAH) 3-methylcholanthrene (3-MC) in rat liver and cultured hepatocytes. MAT1A mRNA levels were reduced by 50% following in vivo administration of 3-MC to adult male rats (100 mg/kg, p.o., 4 days' treatment). This effect was reproduced in a time- and dose-dependent fashion in cultured rat hepatocytes, and was accompanied by the induction of cytochrome P450 1A1 gene expression. This action of 3-MC was mimicked by other PAHs such as benzo[a]pyrene and benzo[e]pyrene, but not by the model arylhydrocarbon receptor (AhR) activator 2,3,7,8-tetrachlorodibenzo-p-dioxin. 3-MC inhibited transcription driven by a MAT1A promoter-reporter construct transfected into rat hepatocytes, but MAT1A mRNA stability was not affected. We recently showed that liver MAT1A expression is induced by AdoMet in cultured hepatocytes. Here, we observed that exogenously added AdoMet prevented the negative effects of 3-MC on MAT1A expression. Taken together, our data demonstrate that liver MAT1A gene expression is targeted by PAHs, independently of AhR activation. The effect of AdoMet may be part of the protective action of this molecule in liver damage.
甲硫氨酸腺苷转移酶（MAT）是一种催化合成S-腺苷甲硫氨酸（AdoMet）的关键酶，AdoMet是最重要的生物甲基供体。肝脏MAT I/III是MAT1A基因的产物。在诸如酒精性肝病和肝硬化等病理条件下，肝脏MAT I/III活性和MAT1A表达会受到损害，并且该基因在肝脏发生肿瘤转化时会沉默。在本研究中，我们评估了大鼠肝脏和培养的肝细胞中多环芳烃（PAH）3-甲基胆蒽（3-MC）是否能够靶向MAT1A的表达。对成年雄性大鼠进行体内给予3-MC（100 mg/kg，口服，4天治疗）后，MAT1A mRNA水平降低了50%。这种效应在培养的大鼠肝细胞中以时间和剂量依赖性方式重现，并伴随着细胞色素P450 1A1基因表达的诱导。3-MC的这种作用被其他多环芳烃如苯并[a]芘和苯并[e]芘模拟，但未被模型芳烃受体（AhR）激活剂2,3,7,8-四氯二苯并对二恶英模拟。3-MC抑制转染到大鼠肝细胞中的MAT1A启动子-报告基因构建体驱动的转录，但MAT1A mRNA稳定性不受影响。我们最近表明，在培养的肝细胞中，AdoMet可诱导肝脏MAT1A表达。在这里，我们观察到外源添加的AdoMet可防止3-MC对MAT1A表达的负面影响。综上所述，我们的数据表明，肝脏MAT1A基因表达是多环芳烃的靶向目标，与AhR激活无关。AdoMet的作用可能是该分子在肝脏损伤中保护作用的一部分。
