title: Growth hormone-independent suppression of growth hormone-dependent female isoforms of cytochrome P450 by the somatostatin analog octreotide.
abstract: 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.
authors.affiliation: Laboratories of Biochemistry, University of Pennsylvania, School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104-6009, USA.
authors.forename: Sarmistha
authors.initials: S
authors.lastname: Banerjee
authors.forename: Rajat Kumar
authors.initials: RK
authors.lastname: Das
authors.forename: Bernard H
authors.initials: BH
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D013006:Growth Hormone / Q000097:blood / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D015282:Octreotide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011986:Receptors, Somatotropin / Q000235:genetics; D013004:Somatostatin / Q000031:analogs & derivatives*
chemical_list: D015415:Biomarkers; D007527:Isoenzymes; D011986:Receptors, Somatotropin; D013004:Somatostatin; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D003577:Cytochrome P-450 Enzyme System; D015282:Octreotide
keywords: CYP; CYP2A1; CYP2C12; CYP2C7; Cytochrome P450; Growth hormone; IGF-1; Octreotide; Ubiquitination; cytochrome P450; insulin-like growth factor-1; qRT-PCR; quantitative reverse transcription polymerase chain reaction