Abstract
Rat liver, as well as other species, contains numerous sex-dependent isoforms of cytochrome P450 (P450) that are regulated by the sexually dimorphic profiles of circulating growth hormone. During puberty, young adulthood, and senescence, changes in the hormonal profiles appear to be responsible for alterations in age-associated expression levels of selective P450 isoforms. In contrast, little is known about the growth hormone secretory profiles and their P450-dependent expression levels during middle age. In the present study, we observed subtle changes in the hormonal concentrations, and frequencies of peaks and interpulse periods in the sexually dimorphic growth hormone profiles of 1-year-old male and female rats correlated to suppression of male-specific isoforms CYP2C11 and CYP2C13 and female-predominant CYP2C7. To identify possible causes for the age-associated changes in the circulating growth hormone profiles, the responsiveness of the hypothalamic-pituitary axis to growth hormone secretagogues clonidine and growth hormone-releasing factor (GRF) were examined in middle-aged male and female rats. In spite of the same sexually dimorphic response in young adult and middle-aged rats to both secretogogues (males > females), the pituitary somatotrophs in the older animals exhibited a dramatic decrease in sensitivity to clonidine, characterized by subnormal growth hormone release levels and an inordinate delay in pituitary response to clonidine stimulation. Results from similar studies conducted on middle-aged arcuate nucleus-lesioned rats suggest that a decline in GRF secretion is a possible contributor to the age-associated alterations in plasma growth hormone profiles during middle age. These changes in GRF-induced, sexually dimorphic secretory growth hormone profiles and the accompanying decline in P450 expression levels may anticipate similar, but more profound, changes to occur during senescence.
Footnotes
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This study was supported by National Institutes of Health Grants HD16358 and GM45758.
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↵2 The interpulse concentrations of growth hormone (i.e. valley nadirs) were corrected, as were all determinations, for the low, apparently nonspecific values found in hypophysectomized serum. Although the corrected average nadir concentrations of the hormone in the middle-aged male profiles were at the minimum sensitivity of the assay, they remained at these values when measured in radioimmunoassays with somewhat enhanced sensitivities (e.g., increased specific activity of the iodinated ligand). Moreover, with an average nadir value of 3 ± 3 ng/ml, it is clear that many of the points fell within the sensitivity range of the assay.
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↵3 The dramatic decline in growth hormone pulse heights reported in senescent males (Xu and Sonntag, 1996) and the much smaller reductions observed in the middle-aged males is a highly unlikely factor in aging-associated CYP2C11 suppression. The pulse height in the masculine growth hormone profile is not recognized by the CYP2C11 discriminator as a regulatory signal because pulse amplitudes of only 5 to 10% of normal allow for full CYP2C11 expression (Pampori and Shapiro, 1994; Agrawal and Shapiro, 2000).
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↵4 In addition to male-bias, numerous studies administering secretagogues do not pretreat rats with blocking agents to eliminate the confounding effects of spontaneously secreted growth hormone. Accordingly, we only cite articles comparable to ours in which plasma growth hormone levels are suppressed to a near-zero constant baseline before secretagogue administration.
- Abbreviations used are::
- P450
- cytochrome P450
- GRF
- growth hormone-releasing factor
- MSG
- monosodium glutamate
- DDC
- diethyldithiocarbamate
- Received July 31, 2001.
- Accepted November 1, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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