Bratoeff Eugene, Sainz Teresita, Cabeza Marisa, Heuze Ivonne, Recillas Sergio, Pérez Victor, Rodríguez César, Segura Tania, Gonzáles Juan, Ramírez Elena
Department of Pharmacy, Faculty of Chemistry, National University of Mexico City, Mexico, D.F., Mexico.
J Steroid Biochem Mol Biol. 2007 Oct;107(1-2):48-56. doi: 10.1016/j.jsbmb.2007.03.038. Epub 2007 Jun 8.
In order to study the biological activity of the two novel steroidal carbamates derivatives: 8a and 8b, we determined the concentration of both compounds that inhibit the 50% of the activity of human prostate 5alpha-reductase enzyme, as well as the in vivo effect of these compounds in the weight of hamster prostate and flank organs diameter size. We determined also, the capacity of these steroids to bind to the androgen receptors present in the rat prostate cytosol. Furthermore the activity of these compounds on the mRNA expression of glycerol 3-phosphate acyl transferase (GPAT) in flank organs was analyzed by RT-PCR. This enzyme induces the triglycerides synthesis, which is increased by T in flank organs. The results from this study indicated that steroids 8a and 8b inhibited the human 5alpha-reductase activity. Compound 8b, which contains a bromine atom in the molecule, decreased the inhibitory effect of the human 5alpha-reductase activity, whereas steroid 8a, which lacks a halogen atom did not show any decrease in the activity of this enzyme. The competition studies demonstrated that 8a and 8b did not inhibit mibolerone binding to the androgen receptor present in the rat prostate cytosol. However, the in vivo activity of both steroids was similar; steroids 8a and 8b had a tendency to decrease the weight of the hamster prostate although this parameter was not statistically significant. These compounds also significantly reduced the diameter of the pigmented spot of hamster flank organs, which are androgen dependent skin's pilosebaceous structures. Steroids 8a and 8b, decreased the transcription of mRNA encoding for GPAT in intact hamster's flank organs topically treated in a similar way as in gonadectomized non-treated animals. These results suggest that mRNA encoding for GPAT is induced by DHT in this tissue.
为了研究两种新型甾体氨基甲酸酯衍生物（8a和8b）的生物活性，我们测定了抑制人前列腺5α-还原酶活性50%时这两种化合物的浓度，以及这些化合物对仓鼠前列腺重量和侧腹器官直径大小的体内效应。我们还测定了这些甾体与大鼠前列腺细胞质中雄激素受体结合的能力。此外，通过逆转录聚合酶链反应（RT-PCR）分析了这些化合物对侧腹器官中甘油3-磷酸酰基转移酶（GPAT）mRNA表达的活性。该酶诱导甘油三酯合成，而睾酮（T）会增加侧腹器官中的甘油三酯合成。本研究结果表明，甾体8a和8b抑制人5α-还原酶活性。分子中含有溴原子的化合物8b降低了人5α-还原酶活性的抑制作用，而不含卤素原子的甾体8a并未显示该酶活性有任何降低。竞争研究表明，8a和8b不抑制米勃龙与大鼠前列腺细胞质中雄激素受体的结合。然而，两种甾体的体内活性相似；甾体8a和8b有降低仓鼠前列腺重量的趋势，尽管该参数无统计学意义。这些化合物还显著减小了仓鼠侧腹器官色素沉着斑点的直径，这些斑点是雄激素依赖的皮肤毛囊皮脂腺结构。甾体8a和8b以与未处理的去势动物相似的方式局部处理完整仓鼠的侧腹器官后，降低了编码GPAT的mRNA的转录。这些结果表明，在该组织中，编码GPAT的mRNA是由双氢睾酮（DHT）诱导产生 的。
