Abstract
The dramatic sexual dimorphism in rat hepatic CYPs is determined by gender differences in the circulating GH profiles. Accordingly, each responsive isoform of CYP is induced or suppressed by different components, i.e., signaling elements, in the GH profiles. It was the purpose of this study to determine whether the signaling elements in the sexually dimorphic plasma GH profiles identified in GH-depleted rats are recognized by the hepatic CYPs in intact rats exposed to a multiplicity of signals contained in the normal gender-dependent GH profiles. To accomplish this goal, we imposed (via osmotic minipumps) the continuous feminine GH profile upon normal male rats and superimposed (via intra-atrial catheters) the episodic masculine profile upon normal females. Monitored circulating GH profiles indicated that the administered GH had little or no effect on the normally secreted gender-dependent endogenous profiles. Basically, we observed that the degree of constancy of GH in the circulation (continuous in females and episodic in males) is the primary determinant establishing sexually dimorphic expression of eight hepatic CYPs in intact rats. However, the characteristic expression levels of each isoform observed in male and female rat liver are determined by an interaction of more subtle signals in the GH profiles reflected in the concentration and persistence of the feminine continuous profile as well as the frequency, duration, and amplitude of pulse and interpulse periods in the masculine episodic profile. In the course of the study, unexpected findings led us to compare the effectiveness of s.c.- and i.p.-infused GH and rGH with hGH. Briefly, male- and female-dependent hepatic CYPs were undoubtedly most responsive to rGH infused by i.p.-implanted osmotic pumps.
Footnotes
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Send reprint requests to: Bernard H. Shapiro, Laboratories of Biochemistry, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104-6048. E-mail: shapirob{at}vet.upenn.edu
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↵1 Current address: Scripps Research Institute, LaJolla, CA 92037.
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↵2 Current address: Department of Drug Metabolism, Merck Research Laboratories, PO Box 2000, RY80E-200, Rahway, NJ 07065-0900.
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This work was supported by National Institutes of Health Grants GM45758 and HD16358.
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↵4 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 that 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.
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↵5 At the time of necropsy, the osmotic pumps were removed and found to contain the expected residual amounts of rGH, hGH, or vehicle. Similarly, hormone levels in the residual volumes of the spent syringes (changed daily) delivering the masculine pulsatile GH profile were measured by radioimmunoassay and found to contain 98 ± 7% (mean ± S.D.) of the expected values.
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↵6 Although mRNA levels for all the CYP isoforms measured in this experiment comparing i.p. infusion of rGH and hGH were in agreement with protein and catalytic activities, the data are not presented because of an insufficient number of analyzed sample.
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↵7 As a result of possible differences in metabolism and/or distribution, i.p. GH infusion of 1.25 μg and 10 μg/kg b.wt./h increased plasma concentrations of the hormone in intact rats to only half as much as observed in hypophysectomized rats (Pampori and Shapiro, 1999).
- Abbreviations used are::
- GH
- growth hormone
- CYP
- cytochrome P450
- hGH
- human growth hormone
- rGH
- rat growth hormone
- T 15αOH
- testosterone 15α-hydroxylase
- T 2αOH
- testosterone 2α-hydroxylase
- T 16αOH
- testosterone 16α-hydroxylase
- T 6βOH
- testosterone 6β-hydroxylase
- T 7αOH
- testosterone 7α-hydroxylase
- T 5αred
- testosterone 5α-reductase
- Received July 7, 2000.
- Accepted August 25, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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