Noncanonical suppression of GH-dependent isoforms of cytochrome P450 by the somatostatin analog octreotide.
Octreotide is a potent somatostatin analog therapeutically used to treat several conditions including hyper GH secretion in patients with acromegaly. We infused, over 30 s, octreotide into male rats every 12 h for 6 days at levels considerably greater than typical human therapeutic doses. Unexpectedly, resulting circulating GH profile was characterized by pulses of higher amplitudes, longer durations, and greater total content than normal, but still contained an otherwise male-like episodic secretory profiles. In apparent disaccord, the normally elevated masculine expression levels (protein and/or mRNA) of CYP2C11 (accounting for >50% of the total hepatic cytochrome P450 content), CYP3A2, CYP2C7, and IGF1, dependent on the episodic GH profile, were considerably downregulated. We explain this contradiction by proposing that the requisite minimal GH-devoid interpulse durations in the masculine profile that solely regulate expression of at least CYP2C11 and IGF1 may be sufficiently reduced to suppress transcription of the hepatic genes. Alternatively, we observed that octreotide infusion may have acted directly on the hepatocytes to induce expression of immune response factors postulated to suppress CYP transcription and/or upregulate expression of several negative regulators (e.g. phosphatases and SOCS proteins) of the JAK2/STAT5B signaling pathway that normally mediates the upregulation of CYP2C11 and IGF1 by the masculine episodic GH profile.
Laboratories of Biochemistry, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104-6009, USA.
Rajat Kumar
RK
Das
Sarmistha
S
Banerjee
Bernard H
BH
Shapiro
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D015536:Down-Regulation / Q000187:drug effects*; D020869:Gene Expression Profiling; D013006:Growth Hormone / Q000097:blood / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D015282:Octreotide / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D010903:Pituitary Gland, Anterior / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013004:Somatostatin / Q000031:analogs & derivatives*; D039181:Steroid 16-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism
D008565:Membrane Proteins; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; C494097:Stat5b protein, rat; C548904:insulin-like growth factor-1, rat; D013004:Somatostatin; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C493085:Cyp2c7 protein, rat; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D015282:Octreotide