Growth hormone-independent suppression of growth hormone-dependent female isoforms of cytochrome P450 by the somatostatin analog octreotide

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.