Inadequacy of the Jak/Stat Signal Transduction Pathway to Mediate Episodic Growth Hormone-dependent Regulation of Hepatic CYP2C11

CYP2C11, the most commonly expressed hepatic P450 isoform in male rats, is induced by the masculine “episodic” secretory growth hormone profile. A considerable number of reports have indicated that episodic growth hormone effects are mediated by the activation of the Jak2/Stat5B signal transduction pathway. We observed that restoration of the normal masculine plasma growth hormone pulse in hypophysectomized male rats did indeed rapidly activate (phosphorylate) Jak2; shortly followed by activation and nuclear translocation of Stat5B. Infusion of a growth hormone pulse with an amplitude 10% of the normal height induced a dramatic overexpression of CYP2C11, had little effect activating Jak2, but induced a more rapid and greater accumulation of activated nuclear Stat5B. Restoration of a growth hormone pulse with an amplitude of only 1% of normal had little effect phosphorylating Jak2, activated and translocated to the hepatic nucleus ~70% of the normally induced levels of Stat5B, but had no inductive effect on CYP2C11. Lastly, the hypophysectomized male rat receiving no growth hormone replacement expressed 25-35% normal concentrations of CYP2C11 in spite of no measurable activation of either Jak2 or Stat5B. These results raise concerns regarding the requisite role of the Jak2/Stat5B pathway in mediating episodic growth hormone regulation of CYP2C11. Accordingly, accumulation of activated ERK1 and ERK2 were the only transducers measured in the study not effected by the 1% replacement pulse of GH, and were elevated 2 to 3-fold above normal when the pulse was renaturalized to 10% of physiologic suggesting the possible involvement of MAPK in episodic growth hormone regulation of CYP2C11. This article has not been copyedited and formatted. The final version may differ from this version. Molecular Pharmacology Fast Forward. Published on December 9, 2004 as DOI: 10.1124/mol.104.005454 at A PE T Jornals on N ovem er 7, 2017 m oharm .aspeurnals.org D ow nladed from