Modified expression of cytochrome P450 mRNAs by growth hormone in mouse liver
Introduction
Growth hormone (GH) is a pituitary-derived polypeptide hormone that is released into the circulation in an intermittent or pulsatile pattern and exhibits multiple physiological effects (Lobie and Waxman, 2003). GH release is ultimately regulated by the action of gonadal hormones on the hypothalamus, which gives rise to important sex-differences in the temporal pattern of circulating GH (Jansson et al., 1985). Sex-differences in plasma GH profiles are most dramatic in rodents, but significant male–female differences in the regulation of pituitary GH release also exist in humans (Veldhuis et al., 2001). Sex-dependent differences in plasma GH profiles first emerge at puberty but are set, and ultimately regulated, by gonadal steroid imprinting during the neonatal period (Jansson and Frohman, 1987). The sexually dimorphic plasma GH profiles dictate the sex-dependent effects that GH imparts on body growth rates at puberty and on the sex-dependent expression of cytochrome P450s (P450s) and other liver enzymes (Shapiro et al., 1995, Waxman, 2000). However, how GH differentially influences the expression of sex-dependent and -independent P450s is an important question that is still under investigation.
P450s are heme-containing membrane-bound enzymes that play important roles in the metabolism of endogenous steroids and fatty acids, as well as detoxification of foreign compounds, including many drugs and environmental chemicals (Negishi et al., 1993). Hepatic P450 genes are regulated at the level of transcription initiation by distinct cues that respond to the sexually dimorphic plasma GH profiles (Legraverend et al., 1992, Sundseth et al., 1992). Particular attention has been paid to members of the CYP2 and CYP3 families and to their involvement in hepatic steroid hormone hydroxylation, which differs for each sex and is also subject to postnatal development control (Waxman and Chang, 1995). In rats, pulsatile GH secretion (in males) is required for activation of the male-specific CYP2C11 gene, whereas continuous GH secretion (in females) is essential for activating the female-specific CYP2C12 gene (Mode et al., 1981). Regarding the murine Cyp2a4 and Cyp2d9 genes, the sex-specific expression is hormonally regulated by GH in males, whereas it is constitutive in females (Noshiro and Negishi, 1986). Recently, we demonstrated that the sexually dimorphic expression of CYP2B9 and CYP3A41 is partly due to the sexually dimorphic plasma GH profiles (Sakuma et al., 2002, Sakuma et al., 2004a, Sakuma et al., 2004b). Differences in the levels of expression of these enzymes might contribute to sex-differences in susceptibility to the toxic effects of many medications. While the contribution of GH to the constitutive expression of hepatic sex-specific genes has been relatively thoroughly investigated, limited data have been obtained on the expression of sex-nonspecific gene. It is important to know whether exogenously administered GH plays a role in the expression of sex-specific and -nonspecific P450s.
Neonatal administration of monosodium l-glutamate (MSG) to rats, mice, and possibly other species produces a profound, but rather selective growth hormone deficiency, resulting in a well-defined syndrome characterized by stunted growth and obesity (Olney and Ho, 1970, Shapiro et al., 1989). Affected adults exhibit abnormalities in both the secretion of GH and the expression of P450s (Kaufhold et al., 2002, Agrawal and Shapiro, 1997). Hypothalamic lesions induced by neonatal administration of MSG permanently and rather selectively block GH secretion, resulting in dramatic changes in hepatic monooxygenase activities, reflecting in part the abnormal modulation of some sex-dependent P450s in the rats (Pampori et al., 1991, Waxman et al., 1990a). Since neonatal exposure to MSG has been proven to induce GH-depletion in rats, providing a useful model for studying the regulation by GH of hepatic monooxygenases (Agrawal and Shapiro, 1997, Pampori et al., 1991, Waxman et al., 1990a, Shapiro et al., 1993), it is worth attempting to use a similar model in mice to examine the effect of GH on the expression of mouse hepatic P450 enzymes.
The present study investigated whether GH differently contributed to regulating the expression of sex-dependent genes Cyp2a4, Cyp2b9, Cyp2b10, Cyp2d9, and Cyp3a41, as well as sex-independent Cyp1a2, Cyp2c29, and Cyp3a11 genes in mouse liver. Our observations suggest that the sex-dependent plasma profile of GH (GH archetype) is one of the important determinants for the differential patterns of constitutive expression of mRNAs of P450s. Administration of GH on schedules mimicking the female and male GH archetype to mice provided evidence supporting the role of GH archetype on the modification profile of P450s mRNA expression.
Section snippets
Materials
An Alzet® micro-osmotic pump, model 1007D, was obtained from Durect Corporation (Cupertino, CA). Recombinant human growth hormone (rhGH) and monosodium l-glutamate (MSG) were supplied by Wako Pure Chemical (Osaka, Japan). The TaqMan® Gold RT-PCR kit, TaqMan® Gene Expression Assays, and SYBR® Green PCR Master Mix were products of Applied Biosystems (Branchburg, NJ). All other laboratory chemicals were of the highest available purity from commercial suppliers.
Animals
C57BL/6NCrj mice (Charles River,
Impact of GH on hepatic mRNA expression of P450s in mice neonatally treated with MSG
To investigate the physiological role of GH archetype on the expression of P450 genes, pups were treated with MSG during the early period of life to become profound growth retardation. The expression levels of male-specific1
Discussion
The present study investigated the effect of the sex-specific pattern of GH secretion on the expression of eight sex-dependent and sex-independent P450 genes (Table 1). The observations demonstrated that the GH archetype was a decisive factor for the expression of sex-dependent P450 genes in the adult mouse liver. The mouse neonatally treated with MSG is an experimental model which allows for the non-surgical suppression of the adult GH level with largely unchanged levels of other
Acknowledgements
This work was partly supported by the Tokyo Biochemical Research Foundation (TBRF), Grants-in-Aid from the Japanese Ministry of Education, Culture, Sport, and Science, and the Smoking Research Foundation.
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