Purine and pyrimidine nucleotide patterns of normal, differentiating, and regenerating liver and of hepatomas in rats.
Purine and pyrimidine nucleotide patterns of normal, differentiating, and regenerating liver and of hepatomas in rats.
复制标题
大鼠正常、分化和再生肝脏以及肝癌的嘌呤和嘧啶核苷酸模式。
作者：
R. Jackson;M. Lui;T. Boritzki;H. Morris;G. Weber
在正常肝脏的冷冻钳夹制备物中，在生长速率非常慢（9618 A）、中等（8999）和快速（3924 A）的肝癌中，在再生肝脏中，以及在新生大鼠的肝脏中，阐明了嘌呤和嘧啶核苷酸的模式。通过高压液相色谱法测定核糖核苷酸含量，并通过酶法测定脱氧核苷三磷酸的含量。在肝脏中，脱氧胸苷三磷酸、脱氧胞苷三磷酸、脱氧腺苷三磷酸和脱氧鸟苷三磷酸的含量非常低（1至5.1 nmol/g湿重）。在所有肝癌中，脱氧核苷三磷酸的浓度相对于肝脏增加，并且增加与肿瘤生长速率相关。三磷酸腺苷（ATP）浓度和腺嘌呤核苷酸总量与肿瘤生长速度呈负相关。3924 A肝癌组织中ATP水平下降至正常肝组织浓度的43%。与此相反，三磷酸胞苷和总胞嘧啶核苷酸的含量增加，在所有3个肝肿瘤。3924 A肝癌组织中黄嘌呤核苷含量为正常肝组织的23.3%，三种肝癌组织中鸟苷含量均高于正常肝组织。在肝癌中鸟嘌呤和尿嘧啶核苷酸浓度没有其他一致的变化。在24小时再生肝，胞苷三磷酸和黄嘌呤核苷一磷酸水平高于正常肝值。与肝肿瘤不同，再生的肝具有增加的尿苷核苷酸和正常的ATP浓度。在6日龄大鼠的肝脏中，除了三磷酸胞苷水平增加27%外，核糖核苷酸含量与成年大鼠肝脏的核糖核苷酸含量没有差异。在正常大鼠肝脏中，长达10分钟的缺血导致ATP和其他核苷三磷酸的广泛去磷酸化，降解的材料积累为单磷酸盐和核苷。然而，肝癌3924 A（和其他肝癌在较小程度上）具有维持ATP水平接近正常值10分钟的缺血的能力。这种能力在碘乙酸治疗后丧失，表明在缺血期间维持肝癌3924 A中正常ATP水平与该肿瘤中无氧糖酵解的高活性相关。结果表明，嘧啶和嘌呤核苷酸模式的各个方面与不同生长速度的肝癌的转化或进展有关。在快速生长、分化和再生的肝脏和肝癌3924 A中脱氧核苷三磷酸池的模式表明，这些DNA生物合成的关键前体的浓度在肿瘤中特别增加，这可能赋予肿瘤细胞选择性优势。
Abstract The pattern of purine and pyrimidine nucleotides was elucidated in freeze-clamped preparations of normal liver; in hepatomas of very slow (9618A), intermediate (8999), and rapid (3924A) growth rates; in regenerating liver; and in liver of neonatal rats. The ribonucleotide content was measured by high-pressure liquid chromatography, and that of the deoxyribonucleoside triphosphates was determined by enzymic assays. In the liver, the contents of deoxythymidine triphosphate, deoxycytidine triphosphate, deoxyadenosine triphosphate, and deoxyguanosine triphosphate were very low (1 to 5.1 nmol/g wet weight). The concentrations of deoxyribonucleoside triphosphates were increased relative to liver in all hepatomas, and the rise correlated with the tumor growth rates. Adenosine triphosphate (ATP) concentration and total adenine nucleotide amounts gave a negative correlation with tumor growth rate. The ATP level in hepatoma 3924A was decreased to 43% of the normal liver concentration. By contrast, contents of cytidine triphosphate and of total cytosine nucleotides were increased in all 3 liver tumors. The xanthosine monophosphate content of hepatoma 3924A was 233% of that of normal liver and guanosine monophosphate concentration in all three hepatomas was above the liver values. There were no other consistent changes in the guanine and uracil nucleotide concentrations in the hepatomas. In the 24-hr regenerating liver, the cytidine triphosphate and xanthosine monophosphate levels were higher than normal liver values. Unlike the liver tumors, the regenerating liver had increased uridine nucleotides and normal ATP concentration. In the liver of 6-day-old rats, with the exception of a 27% increase in cytidine triphosphate level, the ribonucleotide contents did not differ from those of adult rat liver. In normal rat liver, a period of ischemia of up to 10 min resulted in extensive dephosphorylation of ATP and other nucleoside triphosphates, with the degraded material accumulating as monophosphates and nucleosides. However, hepatoma 3924A (and the other hepatomas to a much lesser extent) possessed the ability to maintain ATP levels near normal values for 10 min of ischemia. This capability was lost following iodoacetate treatment, suggesting that the maintenance of a normal ATP level in hepatoma 3924A during ischemia was associated with the high activity of anaerobic glycolysis in this tumor. The results indicate that aspects of the pyrimidine and purine nucleotide pattern are linked with transformation or progression in hepatomas of different growth rates. The pattern of deoxynucleoside triphosphate pools in rapidly growing differentiating and regenerating liver and in hepatoma 3924A shows that the concentrations of these key precursors of DNA biosynthesis are particularly increased in the tumor, and this may confer selective advantages on the neoplastic cells.