Middle-Age Alterations in the Sexually Dimorphic Plasma Growth Hormone Profiles: Involvement of Growth Hormone-Releasing Factor and Effects on Cytochrome P450 Expression

Dhir, Ravindra; Dworakowski, Wojciech; Shapiro, Barry A.

doi:10.1124/dmd.30.2.141

Cited by 11 publications

(9 citation statements)

References 42 publications

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“…In this regard, it is possible that aging induced changes in the rates and͞or patterns of hypothalamic growth hormone-releasing hormone and somatostatin secretion, beginning in middle age (41), may be responsible for the changes in the growth hormone profile of senescent animals (17,20,42).…”

Section: Discussionmentioning

confidence: 99%

Interpulse growth hormone secretion in the episodic plasma profile causes the sex reversal of cytochrome P450s in senescent male rats

Dhir

Shapiro

2003

Proc. Natl. Acad. Sci. U.S.A.

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Humans as well as other mammals experience an aging-related decline in drug metabolism as well as a diminution in growth hormone secretion. In the case of rats, these events are more pronounced in senescent males, whose expression of male-specific isoforms of cytochrome P450, the major drug-metabolizing enzymes and constituting Ϸ60 -70% of the total cytochrome P450 in male rat liver, is completely suppressed, whereas female-dependent isoforms are remarkably induced to female-like levels. Overlooked in these independently reported studies is the fact that ''signals'' inherent in the masculine episodic and female continuous growth hormone profiles regulate expression and͞or suppression of the dozen or so sex-dependent cytochrome P450 isoforms in rat liver. Whereas previous studies identified profound reductions in the pulse amplitudes of the masculine growth hormone profile as the cause for the diminished hormone secretion during aging, pulse heights are not recognized by the cytochromes as regulatory signals. Instead, we have shown that just a nominal secretion of growth hormone during the usual growth hormone-devoid interpulse period in the masculine episodic profile can explain the complete repression of male-specific CYP2C11, CYP3A2, and CYP2A2 and induction of female-dependent CYP2C12, CYP2C6, and CYP2A1 observed in senescent male rats. T wo presumably unrelated aging-induced events were first identified in humans: a decline in drug-metabolizing capacity and a reduction in growth hormone secretion. Regarding the former, it is commonly known that the elderly experience abnormally high incidences of adverse drug reactions and toxicities (1, 2), resulting, at least in part, from a decline in drug-metabolizing enzymes (3) and requiring that doses of therapeutic drugs often be reduced in older patients (4). Concerning the latter, an aging-induced reduction in growth hormone secretion is well characterized, secretion declining by Ϸ14% per decade from late puberty as a result of continuously decreasing pulse amplitudes (5, 6). Unfortunately, direct studies on liver drug metabolism and growth hormone regulation in elderly people are scant, and most evidence is derived from animal studies.Although animal research has been much more thorough and invasive than studies conducted in humans, results with animals have been surprisingly consistent with findings from humans. Early investigations using laboratory animals had to limit their analyses to nonspecific drug-metabolizing enzymes whose activities are dependent on the contributions of multiple isoforms of cytochrome P450 (P450). Moreover, the importance of sex was often overlooked by using only the ''preferred'' sex in pharmacotoxicological studies, the male rat, or worse yet, not even recording the sex of the animal. Nevertheless, in agreement with limited human findings (4, 7-9), rodent studies observed an aging-and sex-related decline in the in vivo and in vitro metabolism of different classes of drugs and subnormal baseline concentrations of various components of t...

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Section: Discussionmentioning

confidence: 99%

Interpulse growth hormone secretion in the episodic plasma profile causes the sex reversal of cytochrome P450s in senescent male rats

Dhir

Shapiro

2003

Proc. Natl. Acad. Sci. U.S.A.

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“…Young adult male rats show episodic spikes of GH every 3-3.5 h with undetectable levels between spikes, whereas females have a more continuous secretion of GH with more pulses at lower amplitude and GH detectable between pulses [39]. Middle-aged males and senescent males have a more feminized pattern of GH secretion [39,40], which leads to the feminization of gene expression. Several sex-specific or sex-dominant P450 cytochromes are known to be regulated by sex-specific GH secretion patterns [39 -42].…”

Section: Cytochrome P450s and Feminization Of Gene Expressionmentioning

confidence: 97%

Global effects of vitamin A deficiency on gene expression in rat liver: evidence for hypoandrogenism

McClintick

Crabb

Tian

et al. 2006

The Journal of Nutritional Biochemistry

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“…More specifically, CYP2C11 expression is dependent upon a minimum growth hormone devoid interpulse period in the circulating masculine growth hormone profile that is normally characterized by large (ϳ250 ng/ml) hormone pulses every 3.5 to 4 h interrupted by growth hormone-devoid interpulses of 2.5 to 3 h . As male rats age, the interpulse may be compromised by a reduced duration and/or by the secretion of low concentrations of growth hormone (Dhir et al, 2002), either of which could severely depress CYP2C11 expression (Agrawal and Shapiro, 2001).…”

Section: Discussionmentioning

confidence: 99%

Constitutive and Inducible Hepatic Cytochrome P450 Isoforms in Senescent Male and Female Rats and Response to Low-Dose Phenobarbital

Agrawal

Shapiro²

2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Numerous studies, usually limited to male rodents, have reported an inverse relationship between the age of the animal and the activities of various multi-cytochrome P450-dependent drug-metabolizing enzymes. It has been suggested that the aging-induced decline in hepatic drug-metabolizing capacity is solely a male phenomenon. That is, whereas the levels of male-specific isoforms of P450 decline with senescence, the female-dependent isoforms remain unchanged in females and even increase in male liver. In addition to their baseline activities, induction levels of hepatic monooxygenases have also been reported to decrease with aging. To examine aging-and sex-dependent effects on drug metabolism at a more molecular level, we measured the expression (mRNA, protein, and/or catalytic activity) of a near dozen constitutive and inducible isoforms of P450 in 5-and 23-month-old male and female Sprague-Dawley rats. Moreover, we investigated the induction effects of low concentrations of phenobarbital known to reveal gender differences and the threshold sensitivities of both constitutive and inducible isoforms. With the exception of male-specific CYP2C11 (whose expression declined ϳ70% in aged male rats), we observed little senescence-associated reduction in either preinduction or induction levels of CYP2B1, CYP2B2, CYP3A1, CYP3A2, CYP2C6, CYP2C7, CYP2C12, and CYP2C13 in either male or female rats. Moreover, the sexually dimorphic expression levels apparent at 5 months of age persisted in the old rats.People over 65 years of age represent the fastest growing segment of the population and consume at least one-third of all prescription drugs. Stated another way, 82% of people over 65 use prescription medications (Willcox et al., 1994). Moreover, the high prevalence of polypharmacy in the elderly likely contributes to an abnormally high 20 to 25% incidence of adverse drug reactions and toxicities in this age group (Hunt et al., 1992;Willcox et al., 1994). The generally accepted aging-associated decline in drug disposition is a result of senescent changes in drug absorption, distribution, excretion, and/or metabolism (Schmucker and Lonergan, 1987). Direct studies on liver drug metabolism in elderly humans are scant with most evidence derived from animal studies.In this regard, early investigations using laboratory animals had to limit their analyses to nonspecific multi-P450 2 -dependent drug-metabolizing enzymes. Moreover, the important contribution of sex was often overlooked by using only the "preferred" gender in pharmacotoxicological studies, the male rodent, or worse yet, not even recording the sex of the animal. Last, few investigators considered the effect of strain, a critical factor (Chengelis, 1988) influencing age-associated changes in drug metabolism.One of the earliest studies using rats reported an inverse relationship between age and the metabolism of commonly used model substrates (Kato and Takanaka, 1968). This, as well as additional stud...

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Middle-Age Alterations in the Sexually Dimorphic Plasma Growth Hormone Profiles: Involvement of Growth Hormone-Releasing Factor and Effects on Cytochrome P450 Expression

Cited by 11 publications

References 42 publications

Interpulse growth hormone secretion in the episodic plasma profile causes the sex reversal of cytochrome P450s in senescent male rats

Interpulse growth hormone secretion in the episodic plasma profile causes the sex reversal of cytochrome P450s in senescent male rats

Global effects of vitamin A deficiency on gene expression in rat liver: evidence for hypoandrogenism

Constitutive and Inducible Hepatic Cytochrome P450 Isoforms in Senescent Male and Female Rats and Response to Low-Dose Phenobarbital

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