Differential expression of gender-dependent hepatic isoforms of cytochrome P-450 by pulse signals in the circulating masculine episodic growth hormone profile of the rat.
The masculine profile of growth hormone (GH) secretion characterized by episodic bursts ( approximately 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 approximately 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 approximately 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.
Agrawal
A K
AK
Laboratories of Biochemistry, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104-6084, USA.
Shapiro
B H
BH
D000818:Animals; D015153:Blotting, Western; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D013006:Growth Hormone / Q000097:blood / Q000378:metabolism*; D007016:Hypophysectomy; D008099:Liver / Q000201:enzymology*; D008297:Male; D020033:Protein Isoforms / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012737:Sex Factors; D015398:Signal Transduction / Q000502:physiology; D013974:Thyroxine / Q000494:pharmacology; D013997:Time Factors
D020033:Protein Isoforms; D012333:RNA, Messenger; D013006:Growth Hormone; D003577:Cytochrome P-450 Enzyme System; D013974:Thyroxine