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Vol. 292, Issue 1, 228-237, January 2000
Laboratories of Biochemistry, University of Pennsylvania School of
Veterinary Medicine, Philadelphia, Pennsylvania
The masculine profile of growth hormone (GH) secretion
characterized by episodic bursts (~200-300 ng/ml plasma) every 3.5 to 4 h, separated by interpulse periods devoid of detectable
hormone, was restored at various peak heights to hypophysectomized,
thyroxine-supplemented male rats to determine the minimum signaling
amplitudes of the hormone pulse required to maintain male-like
expression levels of gender-dependent hepatic cytochrome P-450s (CYP
P-450s). Restoration of the pulse to as little as 2.5% of normal
elevated CYP2C11 (the predominant isoform in male liver) protein and
dependent catalytic activities to ~50% of normal, whereas transcript
concentrations increased to 150% of physiologic. Renaturalizing the
masculine plasma GH profile to 5% of normal was sufficient to increase
CYP2C11 protein and catalytic activity to intact levels while further elevating mRNA to ~200% of normal (subsequently declining to intact concentrations with physiologic pulses). In dramatic contrast, CYP2C7
(mRNA and protein) declined to barely detectable levels following
hypophysectomy and remained completely unresponsive to GH until
replaced with the physiologic masculine profile. The repressive effects
of the episodic GH profile on CYP2A2 and CYP3A2 expression similarly
required replacement of near physiologic pulse amplitudes. Exhibiting
an intermediate response to the masculine profile, restoration of 25%
of the normal pulse amplitude was sufficient to significantly elevate
CYP2A1 and CYP2C6 expression levels in hypophysectomized rats. These
findings illustrate the importance of the pulse amplitudes (in addition
to the interpulse periods) in the circulating masculine GH profile as
differential signals regulating the expression and/or repression of
each sex-dependent hepatic P-450 isoform in the rat.
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