Noncanonical suppression of GH-dependent 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, over 30 sec, octreotide into male rats every 12 h for 6 days at levels considerably greater than typical human therapeutic doses. Unexpectedly, resulting circulating growth hormone profile were 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, all dependent on the episodic growth hormone profile, were considerably down-regulated. We explain this contradiction by proposing that the requisite minimal growth hormone-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 up-regulate expression of several negative regulators (e.g., phosphatases, SOCS proteins) of the JAK2/STAT5B signaling pathway that normally mediates the up-regulation of CYP2C11 and IGF1 by the masculine episodic growth hormone profile.

Growth hormone: a newly identified developmental organizer

“…Plasma GH concentrations were determined by a sensitive sandwich ELISA method as described previously (Das et al, 2013a). Procedures for collecting unstressed postnatal plasma as well as adult serial blood sampling for GH determinations have been reported (Pampori et al, 1991a; Banerjee at al., 2015).…”

“…In this regard, we previously reported that adult male rats and men cannot be induced (regardless of GH treatment) to express the normal female profile of hepatic CYPs (Dhir et al, 2006; Pampori and Shapiro, 1999; Thangavel et al, 2004; Thangavel and Shapiro, 2008; Thangavel et al, 2011) nor can adult female rats or women be induced to fully express the masculine CYP profile (Dhir et al, 2006; Thangavel et al, 2006; Thangavel and Shapiro, 2007; Dhir et al, 2007). The response of each of the dozen or so sex-dependent rat CYP isoforms to GH regulation has been described (Thangavel and Shapiro, 2008; Banerjee et al, 2014; Das et al, 2013a). If CYP enzymes were not imprinted, then irrespective of sex, the same adult treatment should produce the same CYP expression levels in males and females.…”

Permanent uncoupling of male-specific CYP2C11 transcription/translation by perinatal glutamate

“…In addition, trunk blood was collected from individual pups, in the morning from 09:00 to 10:00, representing all litters, at 2, 5, 8 and 11 days of age from both MSG- and vehicle-treated male rats. Circulating plasma GH profiles were determined by a sensitive sandwich ELISA method according to Steyn et al (2011) with modifications by us (Das et al, 2013). …”

Irreversible perinatal imprinting of adult expression of the principal sex‐dependent drug‐metabolizing enzyme CYP2C11

“…Repetitive blood samples (40 μl) were obtained at 15‐min intervals from unrestrained, unstressed, and completely conscious hypox, neonatally MSG‐treated, and NaCl‐treated adult rats outfitted with our mobile catheterization apparatus (40) for 8 continuous hours. Circulating plasma GH profiles were determined by a sensitive sandwich ELISA method according to Steyn et al (41) with modifications by us (42).…”