DeRubertis F R, Craven P
Cancer Res. 1977 Jan;37(1):15-21.
Ethionine-induced hepatomas are characterized by high adenylate cyclase activity and cyclic adenosine 3',5'-monophosphate content relative to those of surrounding liver or liver from pair-fed control rats. The present study examined the properties of the guanylate cyclase-cyclic guanosine 3',5'-monophosphate (cGMP) system of these tissues. cGMP levels of the ethionine-induced hepatomas, determined in both specimens quick-forzen in situ and after in vitro incubation of tissue slices, were approximately 2 times higher than those of surrounding liver or controls. Higher cGMP in the tumors was associated with an increase in whole homogenate, soluble, and particulate guanylate cyclase activities, as well as an increase in soluble cGMP-phosphodiesterase activity. 3-Isobutyl-1-methylxanthine, a potent inhibitor of cGMP-phosphodiesterase activity, potentiated the differences in cGMP between slices of the hepatomas and surrounding liver or control, suggesting that the higher steady-state cGMP content of the tumors reflected enhanced basal cGMP synthesis which was partially offset by increased nucleotide degradation. In the hepatomas, a greater proportion of the total guanylate cyclase activity was located in the particulate cell fraction (31%) as compared to the subcellular distribution of enzyme activity in either surrounding liver or controls (15% of total in the particulate fraction). Carbamylcholine, which increased cGMP 3-fold in surrounding liver and controls, failed to alter cGMP levels inslices of hepatoma. Further, the relative changes in both cGMP accumulation and guanylate cyclase activity of the tumors in response to NaN3, NH2OH, and NaNO2 were blunted compared to surrounding liver or controls, although in each instance a response was clearly evident. Ethionine-induced hepatomas are thus characterized by: (a) significant increases in cGMP content and in guanylate cyclase and cGMP-phosphodiesterase activities, (b) a change in the subcellular distribution of guanylate cyclase, and (c) altered responsiveness of the guanylate cyclase-cGMP system to several agonists.
相对于周围肝脏或配对喂养对照大鼠的肝脏，乙硫氨酸诱导的肝癌具有较高的腺苷酸环化酶活性和环磷酸腺苷含量。本研究检测了这些组织的鸟苷酸环化酶 - 环磷酸鸟苷（cGMP）系统的特性。在原位快速冷冻的标本以及组织切片体外孵育后测定的乙硫氨酸诱导的肝癌组织中的cGMP水平，比周围肝脏或对照组织高约2倍。肿瘤中较高的cGMP与全匀浆、可溶性和颗粒性鸟苷酸环化酶活性的增加以及可溶性cGMP磷酸二酯酶活性的增加有关。3 - 异丁基 - 1 - 甲基黄嘌呤是一种有效的cGMP磷酸二酯酶活性抑制剂，它增强了肝癌组织切片与周围肝脏或对照组织之间cGMP的差异，这表明肿瘤中较高的稳态cGMP含量反映了基础cGMP合成的增强，而这种增强部分被核苷酸降解的增加所抵消。在肝癌组织中，与周围肝脏或对照组织中酶活性的亚细胞分布相比（颗粒部分占总量的15%），总鸟苷酸环化酶活性中更大比例位于颗粒细胞部分（31%）。氨甲酰胆碱可使周围肝脏和对照组织中的cGMP增加3倍，但未能改变肝癌组织切片中的cGMP水平。此外，与周围肝脏或对照组织相比，肿瘤组织中cGMP积累和鸟苷酸环化酶活性对NaN₃、NH₂OH和NaNO₂的相对变化较为迟钝，尽管在每种情况下反应都明显可见。因此，乙硫氨酸诱导的肝癌具有以下特征：（a）cGMP含量、鸟苷酸环化酶和cGMP磷酸二酯酶活性显著增加；（b）鸟苷酸环化酶亚细胞分布的改变；（c）鸟苷酸环化酶 - cGMP系统对几种激动剂的反应性改变。
