Röttgen V, Rabes H M
Institute of Pathology, University of Munich, F.R.G.
Biochim Biophys Acta. 1989 Sep 15;992(3):349-54. doi: 10.1016/0304-4165(89)90095-0.
Hydroxyurea (HU) causes inhibition of DNA synthesis in regenerating rat liver due to an inhibition of the ribonucleotide reductase. We studied the consequences of a continuous HU infusion for deoxyribonucleoside triphosphate (dNTP) pools in the liver after partial hepatectomy and tried to modify imbalances by application of deoxyribonucleosides in vivo. In normal liver, an intracellular concentration of 0.16, 0.84, 0.33 and 0.27 pmol/micrograms DNA was observed for dATP, dCTP, dGTP and dTTP, respectively. In regenerating liver the dNTP pools show minor changes until 18 h after partial hepatectomy. During and after a continuous HU infusion 14--24 h after partial hepatectomy, the intracellular dNTP pools change considerably. At 19.5 h after partial hepatectomy, 5.5 h after the start of HU infusion, and at 25 h after partial hepatectomy, 1 h after termination of HU infusion, the dTTP pool was more than 10-times, and the dGTP pool about 2-times higher than in controls, while the dATP and dCTP pools remain relatively unchanged. Simultaneous infusion of HU and deoxythymidine (dThd) 14--25 h after partial hepatectomy results in a further increase of the dTTP pool during and after HU infusion. Administration of deoxycytidine (dCyd) leads to a moderate increase of the dCTP pool and a weak decrease of the dTTP pool during HU infusion. The combined application of dCyd and dThd after HU infusion had similar effects on dNTP pools as observed with dThd alone. These results show that intracellular pools of dNTPs in hepatocytes can be altered by exogenous factors in a controlled pattern. This system can be used as a model for studying the implications of induced dNTP pool dysbalances for the initiation of liver carcinogenesis by mutagenic chemicals.
羟基脲（HU）由于抑制核糖核苷酸还原酶而导致再生大鼠肝脏中的DNA合成受到抑制。我们研究了在部分肝切除术后持续输注HU对肝脏中脱氧核糖核苷三磷酸（dNTP）池的影响，并试图通过在体内应用脱氧核苷来改善这种失衡。在正常肝脏中，观察到dATP、dCTP、dGTP和dTTP在细胞内的浓度分别为0.16、0.84、0.33和0.27 pmol/微克DNA。在再生肝脏中，直到部分肝切除术后18小时，dNTP池显示出微小变化。在部分肝切除术后14 - 24小时持续输注HU期间及之后，细胞内dNTP池发生显著变化。在部分肝切除术后19.5小时、HU输注开始后5.5小时，以及部分肝切除术后25小时、HU输注终止后1小时，dTTP池比对照组高出10倍以上，dGTP池约高出2倍，而dATP和dCTP池保持相对不变。在部分肝切除术后14 - 25小时同时输注HU和脱氧胸苷（dThd）会导致在HU输注期间及之后dTTP池进一步增加。在HU输注期间，给予脱氧胞苷（dCyd）会导致dCTP池适度增加，dTTP池轻微下降。HU输注后联合应用dCyd和dThd对dNTP池的影响与单独应用dThd时相似。这些结果表明，肝细胞内的dNTP池可被外源性因素以可控方式改变。该系统可作为一个模型，用于研究诱导的dNTP池失衡对诱变化学物质引发肝癌的影响。
