Abstract
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.
Footnotes
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Send reprint requests to: Bernard H. Shapiro, Laboratories of Biochemistry, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce St., Philadelphia, PA 19104-6084. E-mail:shapirob{at}vet.upenn.edu
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↵1 This work was supported by National Institutes of Health Grants GM45758 and HD16358.
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↵2 Current address: Department of Drug Metabolism, Merck Research Laboratories, P.O. Box 2000, RY80-A9, Rahway, NJ 07065-0900.
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↵4 A comparison of the benefits and limitations of the growth hormone-deficiency models in studies of P-450 regulation has been addressed elsewhere (Shapiro et al., 1993, 1995).
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↵5 Normal expression levels of hepatic CYP2C7 require both growth hormone and retinoids [i.e., vitamin A and its metabolites (Westin et al., 1997)]. Because retinoid metabolism is also growth hormone-dependent (Westin et al., 1997), it is possible that the subnormal replacement levels of the hormone were insufficient to generate the obligatory concentrations of retinoid metabolites needed for normal restoration of CYP2C7.
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↵6 We reported a similar overexpression of hepatic female-dependent CYP2C12 in low dose MSG-treated female rats exhibiting a 75 to 85% permanent reduction in the continuous feminine growth hormone profile (Pampori and Shapiro, 1994a). This overexpression, however, was not observed in the hypophysectomized female rat infused with subphysiologic feminine plasma growth hormone profiles (Pampori and Shapiro, 1996).
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↵7 The gender-dependent isoforms may not be the only P-450s regulated by the pulse amplitudes as the repressive effects of the masculine plasma growth hormone profile on phenobarbital induction of nonconstituent CYP2B1 and CYP2B2 are also directly proportional to the pulse amplitudes (Shapiro et al., 1994).
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↵3 The terms sex-dependent, sex-predominant or dominant, and sex-specific are often used indiscriminately. We use sex- or gender-dependent to imply that expression levels are dependent on the existence of gender; sex- or gender-predominant indicates expression levels, regardless of magnitude, are consistently greater in one gender; and sex- or gender-specific implies that expression is basically restricted to only one gender.
- Abbreviations:
- CYP P-450
- cytochrome P-450
- GH
- growth hormone
- MSG
- monosodium glutamate
- rGH
- rat growth hormone
- hGH
- human growth hormone
- bGH
- bovine growth hormone
- Stat5b
- signal transducer and activator of transcription 5b
- JAK2
- Janus kinase 2
- Received June 28, 1999.
- Accepted September 14, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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