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

Eur J Pharmacol. 2013 Sep 5;715(1-3):256-61. doi: 10.1016/j.ejphar.2013.05.013. Epub 2013 May 21.

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.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism*
  • Female
  • Gene Expression Regulation, Enzymologic / drug effects
  • Growth Hormone / blood
  • Growth Hormone / metabolism
  • Insulin-Like Growth Factor I / genetics
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Octreotide / administration & dosage
  • Octreotide / analogs & derivatives*
  • Octreotide / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Somatotropin / genetics
  • Somatostatin / analogs & derivatives*

Substances

  • Biomarkers
  • Isoenzymes
  • Receptors, Somatotropin
  • Somatostatin
  • Insulin-Like Growth Factor I
  • Growth Hormone
  • Cytochrome P-450 Enzyme System
  • Octreotide