Inhibition of prolyl 4-hydroxylase in vitro and in vivo by members of a novel series of phenanthrolinones
Inhibition of prolyl 4-hydroxylase in vitro and in vivo by members of a novel series of phenanthrolinones
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DOI：
10.1042/bj3530333
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发表时间：
2001-01-15
影响因子：
4.1
通讯作者：
Stephenson, R
中科院分区：
文献类型：
--
作者：
Franklin, TJ;Morris, WP;Stephenson, R
一系列新的菲咯啉酮类化合物的实例被证明是禽脯氨酰4-羟化酶和胶原羟化的有效竞争性抑制剂，在体外的鸡胚腱细胞和人包皮成纤维细胞中以及在体内的雌二醇刺激的大鼠子宫中。选择在俄亥俄州具有相当效力的两种化合物，化合物1（1，4-二氢菲咯啉-4-酮-3-羧酸）和化合物5 [8-（N-丁基-N-乙基氨基甲酰基）-1，4-二氢菲咯啉-4-酮-3-羧酸]，以研究抑制新合成的子宫胶原的羟基化对该蛋白体内周转的影响。羟基化抑制率超过50%，持续时间约为单次口服化合物后8小时，在此期间胶原蛋白中放射性标记的脯氨酸和4-羟脯氨酸显着损失。随着化合物的抑制作用下降，胶原蛋白在48小时内进行性羟基化，伴随着子宫胶原蛋白放射性标记的损失减少。早期的报道表明，在脯氨酰4-羟化酶失活的细胞中的内质网内积累的羟基化不足的胶原蛋白缓慢降解，但当脯氨酰4-羟化酶的活性恢复时，然后迅速羟基化并分泌。与目前的结果，这表明，潜在的使用脯氨酰4-羟化酶抑制剂，以控制过度的胶原蛋白沉积在病理性纤维化可能受到限制，需要保持连续抑制胶原蛋白羟基化，以促进细胞内降解的积累的蛋白质。
Examples of a novel series of phenanthrolinones are shown to be potent competitive inhibitors of avian prolyl 4-hydroxylase, and of collagen hydroxylation, in embryonic chick tendon cells and human foreskin fibroblasts in vitro and in the oestradiol-stimulated rat uterus in vivo. Two compounds, Compound 1 (1,4-dihydrophenanthrolin-4-one-3-carboxylic acid) and Compound 5 [8-(N-butyl-N-ethylcarbamoyl)-1,4-dihydrophenathrolin-4-one-3-carboxylic acid], with comparable potencies in ohio, were chosen to investigate the effect of the inhibition of the hydroxylation of newly synthesized uterine collagen on the turnover of this protein inf vivo. Inhibition of hydroxylation by more than 50 % for approx. 8 h following single oral doses of the compounds was associated with significant losses of radiolabelled proline and 4-hydroxyproline from collagen during this period. Progressive hydroxylation of collagen over 48 h, as the inhibitory action of the compounds declined, was accompanied by a decreased loss of radiolabel from the uterine collagen. Earlier reports indicated that underhydroxylated collagen, accumulating within the endoplasmic reticulum in cells where prolyl 4-hydroxylase is inactivated: is slowly degraded, but is then rapidly hydroxylated and secreted when the activity of prolyl 4-hydroxylase is restored. Taken with the present results, this suggests that the potential use of inhibitors of prolyl 4-hydroxylase to control excessive collagen deposition in pathological fibrosis may be limited by the need to maintain continuous inhibition of collagen hydroxylation so as to facilitate intracellular degradation of the accumulated protein.