年龄对大鼠皮质体外合成γ-氨基丁酸能甾体5-α-孕烷-3,20-二酮和5-α-孕烷-3-α-醇-20-酮的影响。

Effect of age on synthesis of the GABAergic steroids 5-alpha-pregnane-3,20-dione and 5-alpha-pregnane-3-alpha-ol-20-one in rat cortex in vitro.

作者信息

Stuerenburg H J, Fries U, Iglauer F, Kunze K

机构信息

Department of Neurology, University Hospital Hamburg-Eppendorf, Federal Republic of Germany.

出版信息

J Neural Transm (Vienna). 1997;104(2-3):249-57. doi: 10.1007/BF01273185.

DOI:10.1007/BF01273185

PMID:9203086

Abstract

Progesterone 5-alpha-reductase activity and 3-alpha-hydroxysteroid dehydrogenase activity were determined in the cortex of male and female rats in vitro. Age effects were investigated. The age of the male rats was 3-23 months, and that of the female rats 4-23 months. On addition, we investigated the enzyme 3 beta-hydroxysteroid oxidoreductase, 5-ene-isomerase in rat cortex in order to estimate the local synthesis of progesterone from pregnenolone. We found age-related increases in progesterone 5-alpha-reductase activity in the female rats (r = 0.64, p < 0.01, n = 6) and in the male rats (r = 0.5, p < 0.05, n = 18). 3-alpha-HSDH activity remained constant with age in female and male rats. The ratio of 3-alpha-hydroxysteroid dehydrogenase activity to 5-alpha-reductase activity tended to decrease with age (not significantly) in both male rats (r = -0.45, p = 0.06, n = 19) and the female rats (r = -0.36, p = 0.17, n = 16). We could not detect significant metabolism of pregnenolone to progesterone in rat cortex in vitro. The sensitivity of the assays of 3 beta-hydroxysteroid oxidoreductase, 5-ene-isomerase was calculated from the mean of the blank values + 3SD; the sensitivity of the assay was calculated as 0.103 fmol/mg protein/min. No significant metabolism of pregnenolone could be detected in cortex pooled from several male rats. The mean metabolism of progesterone was 1,200 times higher than the detection threshold of the assay for 3 beta-hydroxysteroid oxidoreductase, 5-ene-isomerase. We conclude that modifications of the inhibitory effects of the GABAergic steroids 5-alpha-pregnane-3,20-dione and 5-alpha-pregnane-3-alpha-ol-20-one via altered progesterone metabolism in rat cortex are possible with aging. A connection with the age-related increase in incidence of epileptic attacks, and with age-related changes in the effects of anticonvulsant and GABAA-active drugs, appears possible.

摘要

在体外测定了雄性和雌性大鼠皮质中的孕酮5-α-还原酶活性和3-α-羟基类固醇脱氢酶活性。研究了年龄的影响。雄性大鼠的年龄为3至23个月，雌性大鼠的年龄为4至23个月。此外，我们研究了大鼠皮质中的3β-羟基类固醇氧化还原酶、5-烯异构酶，以评估孕烯醇酮向孕酮的局部合成。我们发现，雌性大鼠（r = 0.64，p < 0.01，n = 6）和雄性大鼠（r = 0.5，p < 0.05，n = 18）的孕酮5-α-还原酶活性均随年龄增长而增加。3-α-HSDH活性在雌性和雄性大鼠中均不随年龄变化。在雄性大鼠（r = -0.45，p = 0.06，n = 19）和雌性大鼠（r = -0.36，p = 0.17，n = 16）中，3-α-羟基类固醇脱氢酶活性与5-α-还原酶活性的比值均有随年龄下降的趋势（但不显著）。我们在体外未检测到大鼠皮质中孕烯醇酮向孕酮的显著代谢。3β-羟基类固醇氧化还原酶、5-烯异构酶测定的灵敏度是根据空白值的平均值 + 3个标准差计算得出的；测定的灵敏度计算为0.103 fmol/mg蛋白质/分钟。在几只雄性大鼠的皮质混合样本中未检测到孕烯醇酮的显著代谢。孕酮的平均代谢比3β-羟基类固醇氧化还原酶、5-烯异构酶测定的检测阈值高1200倍。我们得出结论，随着年龄增长，大鼠皮质中孕酮代谢改变可能会改变γ-氨基丁酸能类固醇5-α-孕烷-3,20-二酮和5-α-孕烷-3-α-醇-20-酮的抑制作用。这似乎可能与癫痫发作发生率随年龄增长的增加以及抗惊厥药和GABAA活性药物作用的年龄相关变化有关。