Marie S, Cresteil T
INSERM U 75, CHU Necker, Paris, France.
Biochim Biophys Acta. 1989 Dec 22;1009(3):221-8. doi: 10.1016/0167-4781(89)90106-1.
The expression of phenobarbital-, pregnenolone 16 alpha-carbonitrile- and polycyclic aromatic hydrocarbon-inducible cytochromes P-450 and of phenobarbital-inducible UDP-glucuronosyltransferase was examined in developing rat liver. RNAs coding for these proteins were present in fetal rat liver and their respective concentrations remained quite stable in non-induced animals. Inducers differently affected the concentration of RNAs: clofibrate had no action, whereas methylcholanthrene was highly active in fetal liver. Induction by phenobarbital gradually increased during ontogenesis, in parallel with the augmentation of the number of hepatocyte cells in the liver. Our contribution definitively demonstrates that the ability of phenobarbital to enhance P-450 and UDPGT RNAs is strictly restricted to hepatocytes and remains roughly unchanged throughout ontogenesis. In addition, phenobarbital was also able to potentiate the inducing capacity of methylcholanthrene (i.e., raising the TCDD-binding protein) exclusively in hepatocytes. This is the first direct evidence that the number of hepatocytes in the liver, rather than a biochemical maturation, controls the expression of phenobarbital-inducible genes. Pregnenolone 16 alpha-carbonitrile was also effective as inducer in fetal and neonatal rats and its maximal effect was observed in 5-d-old neonates, suggesting a regulation mechanism temporally different from that of phenobarbital.
在发育中的大鼠肝脏中，检测了苯巴比妥、孕烯醇酮16α-碳腈和多环芳烃诱导的细胞色素P-450以及苯巴比妥诱导的UDP-葡萄糖醛酸基转移酶的表达。编码这些蛋白质的RNA存在于胎鼠肝脏中，在未诱导的动物中它们各自的浓度保持相当稳定。诱导剂对RNA浓度的影响各不相同：氯贝丁酯没有作用，而甲基胆蒽在胎肝中活性很高。苯巴比妥的诱导作用在个体发育过程中逐渐增强，与肝脏中肝细胞数量的增加同步。我们的研究明确表明，苯巴比妥增强P-450和UDPGT RNA的能力严格限于肝细胞，并且在整个个体发育过程中大致保持不变。此外，苯巴比妥还能够仅在肝细胞中增强甲基胆蒽的诱导能力（即提高TCDD结合蛋白）。这是第一个直接证据，表明肝脏中肝细胞的数量而非生化成熟度控制着苯巴比妥诱导基因的表达。孕烯醇酮16α-碳腈在胎鼠和新生大鼠中也是有效的诱导剂，其最大作用在5日龄新生大鼠中观察到，这表明其调控机制在时间上与苯巴比妥不同。
