Laboratories of Biochemistry, University of Pennsylvania, School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104-6009, USA.
Eur J Pharmacol. 2013 Sep 5;715(1-3):256-61. doi: 10.1016/j.ejphar.2013.05.013. Epub 2013 May 21.
Octreotide is a potent somatostatin analog therapeutically used to treat several conditions including hyper growth hormone secretion in patients with acromegaly. We infused octreotide into female Sprague Dawley rats every 12h for 6 days at levels considerably greater than typical human therapeutic doses. Resulting circulating growth hormone profiles were characterized by ∼25% reduction in plasma levels, including both pulse and interpulse components, but still contained in an otherwise female-like "continuous" secretory profile. The normally elevated feminine expression levels (protein and/or mRNA) of CYP2C12, CYP2A1, CYP2C7 and insulin-like growth factor-1 (IGF-1), all dependent on the continuous feminine growth hormone profile, were dramatically down-regulated. Octreotide suppression of the female-dependent levels of CYPs (cytochromes P450) and IGF-1 could not be explained by the apparently inconsequential alterations in the feminine circulating growth hormone profile. In this regard, somatostatin and its analogs are known to have a myriad of extra-pituitary actions effecting nearly all tissues in the body. Focusing our attention on CYP2C12, accounting for >40% of the total hepatic cytochrome P450 content in the female rat liver, we found a ∼4-fold increase in hepatic ubiquitin-CYP2C12 levels in octreotide treated rats suggesting a possible contributing factor for the >60% suppression of CYP2C12 protein concentrations.
奥曲肽是一种有效的生长抑素类似物，临床上用于治疗多种疾病，包括肢端肥大症患者的生长激素过度分泌。我们以远高于典型人类治疗剂量的水平，每 12 小时向雌性 Sprague Dawley 大鼠输注奥曲肽，持续 6 天。结果表明，循环生长激素谱的特征是血浆水平降低约 25%，包括脉冲和脉冲之间的成分，但仍保持女性特有的“连续”分泌模式。正常情况下，CYP2C12、CYP2A1、CYP2C7 和胰岛素样生长因子-1（IGF-1）的雌性表达水平（蛋白和/或 mRNA）升高，这些都依赖于连续的雌性生长激素谱，而这些表达水平都被显著下调。奥曲肽对 CYP（细胞色素 P450）和 IGF-1 的雌性依赖性水平的抑制作用不能用女性循环生长激素谱的明显无关变化来解释。在这方面，生长抑素及其类似物具有多种垂体外作用，影响几乎身体所有组织。我们将注意力集中在 CYP2C12 上，它在雌性大鼠肝脏中占总肝细胞色素 P450 含量的>40%，我们发现奥曲肽处理大鼠的肝内泛素-CYP2C12 水平增加了约 4 倍，这表明可能是 CYP2C12 蛋白浓度抑制>60%的一个促成因素。
