Received for publication June 29, 2007.
Revised July 30, 2007.
Accepted for publication August 1, 2007.

ATTENUATED EXPRESSION OF EPISODIC GROWTH HORMONE-INDUCED CYP2C11 IN FEMALE RATS ASSOCIATED WITH SUBOPTIMAL ACTIVATION OF THE JAK2/STAT5B AND OTHER MODULATING SIGNALING PATHWAYS

Abstract

Inherent sex differences in various parameters of growth, musculoskeletal function, metabolism and cytochrome P450-dependent drug metabolism have been reported in rats and humans administered the typical intermittent/episodic growth hormone (GH) replacement therapy. Having infused and monitored the identical physiologic masculine (episodic) growth hormone profile to both hypophysectomized male and female rats, we observed that induction levels of hepatic CYP2C11 were 35-40% lower in females. Associated with the reduced expression of the P450 isoform in the episodic GH-treated females were dramatically lower activation levels of Janus kinase (Jak2), signal transducers and activators of transcription (Stat5A and 5B) as well as 50% less binding of Stat5B to the CYP2C11 promoter. Since the Jak2/Stat5B signaling pathway mediates the effects of the masculine GH profile on its target cells, we conclude that the lower induction level of CYP2C11 in females exposed to the masculine GH profile is likely due, at least in part, to the suboptimum activation of the Jak2/Stat5B pathway. In addition to the reduced activation of the Jak2/Stat5B pathway, we observed lower activational levels of mitogen-activated protein kinase (p44/42 MAPK) and indirectly, nuclear factor-kappa B (NF-B) in the episodic GH-treated females that may be involved in attenuating the activity of the Jak2/Stat5B pathway diminishing CYP2C11 expression levels.

Key words: CYP expression, cytochrome P450, cytochrome P450 isoforms, cytochrome P450 regulation, gender differences, JAK-STAT, liver microsomes, sexual dimorphism, transcriptional regulation

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