On the obligatory role of the hypophysis in sexual differentiation hepatic metabolism in rats.

Gustafsson, Jan‐Åke; Stenberg, Åke

doi:10.1073/pnas.73.5.1462

Cited by 46 publications

(24 citation statements)

References 24 publications

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“…These alterations are not likely attributable to liver necrosis because the non-sex-differentiated 7α-hydroxylation and the female-specific 5α reduction of androstenedione were unaffected in the male liver. Because these results somewhat resemble the effects of hypophysectomy (43), the observed attenuation of sex differentiation is more likely related to the pituitary damage, although it is difficult to interpret why the GH level is decreased only slightly on day 3 without analysis of its secretory pattern. In addition, it cannot be excluded at this point that DEN may affect the hypothalamus and/or gonads, which in turn influences the sex differentiation of certain liver metabolism.…”

Section: Discussionmentioning

confidence: 82%

Diethylnitrosamine causes pituitary damage, disturbs hormone levels, and reduces sexual dimorphism of certain liver functions in the rat.

Liao

Blanck

Eneroth

et al. 2001

Environ Health Perspect

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The acute toxicity of diethylnitrosamine (DEN) to the liver has been well documented in the literature, but whether DEN also affects the endocrine parameters has been addressed in only a few studies. We thus investigated the effects of DEN on pituitary, serum hormone levels, and certain sex-differentiated liver enzymes in this study. Adult male Wister rats were intraperitoneally injected with DEN at a single dose of 200 mg/kg and were sacrificed at 1, 3, 7, and 35 days after injection; DEN-treated females were included as controls at days 7 and 35. Electron microscopic observation showed that during the first week after injection, all types of granular cells of the anterior pituitary in male animals exhibited cellular damage, including disrupted organelles and cellular structure, as well as pyknotic or lytic nuclei. Many undamaged secretory cells exhibited dilated endoplasmic reticula, hypertrophic Golgi complexes, and peripheral location of secretory granules, which usually are morphologic features of increased cellular activities. In male rats, the serum level of total testosterone decreased and the corticosterone increased 1 day after DEN treatment. The serum level of growth hormone (GH) decreased and the prolactin level increased on day 3. The hepatic expression of the male-specific cytochrome P450 2C11 (CYP2C11) decreased to 1-5% of the normal levels during the first week and was still 50% lower than the normal level on day 35, whereas the female-specific CYP2C12 expression increased only slightly. Activities of the male predominant 16alpha, 16beta, and 6beta hydroxylation of androstenedione by microsome decreased in an in vitro assay, whereas the non-sex-differentiated 7alpha hydroxylation and the female-predominant 5alpha reduction of androstenedione were unaffected. In female rats, decreased serum GH level was observed on day 7. The CYP2C12 expression in females was decreased to about 1% and 80% of the normal levels on day 7 and day 35, respectively, but the CYP2C11 expression was unchanged. These data suggest that in male rats, DEN treatment may cause pituitary damage, disturb serum hormone levels, and induce long-lasting reduction of sexual dimorphism in certain liver functions.

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Section: Discussionmentioning

confidence: 82%

Diethylnitrosamine causes pituitary damage, disturbs hormone levels, and reduces sexual dimorphism of certain liver functions in the rat.

Liao

Blanck

Eneroth

et al. 2001

Environ Health Perspect

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“…Androgen and estrogen are apparently involved in the expression of sex-related differences in drug and steroid hydroxylations (1 , 3, 33). Moreover, the pituitary gland also plays an essential role in the sex-related differences in drug and steroid hydroxylations (18,19). Growth hormone has been postulated as a responsible factor (18,20,34,35).…”

Section: Discussionmentioning

confidence: 99%

“…On the basis of catalytic activities, N-terminal amino acid sequences and other properties, P-450 2c, and P-450 5R and P-450i are probably identical with or have a close resemblance to P-450-male and P-450-female, respectively (12,17). On the other hand, the involvement of the pituitary gland in the occurrence of sex differ ences induced by gonadal hormones in drug and steroid metabolisms in rat liver micro somes has been demonstrated (3,(18)(19)(20). Growth hormone has been postulated to be the responsible factor in the pituitary gland.…”

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confidence: 99%

Effects of Hypophysectomy and Growth Hormone Treatment on Sex-Specific Forms of Cytochrome P-450 in Relation to Drug and Steroid Metabolisms in Rat Liver Microsomes

Yamazoe

Shimada

Kamataki

et al. 1986

Japanese Journal of Pharmacology

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Abstract-Hypophysectomy decreased the content of a male specific cytochrome P-450, P-450-male, in male rats, while it expressed P-450-male and completely depressed a female specific cytochrome P-450, P-450-female, in female rats. Intermittent injections of human growth hormone (GH), which mimic the secretion in males, restored P-450-male in hypophysectomized (Hypox) male rats and partially restored P-450-female in Hypox female rats. Continuous infusion of GH, which mimics the female secretion pattern, into Hypox male rats caused a further decrease in P-450-male content, and it caused the expression of P-450-female. In Hypox female rats, the same treatment depressed P-450-male and expressed P-450-female to the level of an intact female. These results indicate that the diurnal changes in the pattern of serum growth hormone level regulate the expression of P-450-male and P-450-female. The activities of testosterone 2a and 16a hydroxylases were closely correlated to P-450-male content with the correlation coefficients (r) of 0.955 and 0.929, respectively. Benzo(a)pyrene hydroxylation was also correlated to P-450-male content (r=0.850).Aminopyrine N-deme thylation and propoxycoumarin 0-depropylation were correlated to less extents (r=0.692 and r=0.720), while aniline hydroxylation and 0-ethylresorufin 0 deethylation were not correlated to P-450-male content. These results indicate that testosterone 2a and 16a-hydroxylations are closely dependent, but the metabolism of a variety of drugs are dependent to different extents on P-450-male in rat liver microsomes.

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“…Gustafsson and Stenberg (1976) first suggested the existence of a pituitary factor that feminizes steroid metabolism by rat liver microsomes and called it "a feminization factor". Later, this pituitary factor was found to be GH (Kramer and Colby, 1976).…”

mentioning

confidence: 99%

Developmental Action of Estrogen Receptor-α Feminizes the Growth Hormone-Stat5b Pathway and Expression ofCyp2a4andCyp2d9Genes in Mouse Liver

Sueyoshi¹,

Yokomori²,

Korach³

et al. 1999

Mol Pharmacol

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We have studied the roles of estrogen receptor-␣ (ER␣) and the Stat5b form of STAT (signal transducers and activators of transcription) in sex-specific expression of Cyp2a4 (steroid 15␣-hydroxylase) and Cyp2d9 (steroid 16␣-hydroxylase) genes using ER␣-deficient mice. ER␣ deficiency resulted in the repression of the female-specific Cyp2a4 and expression of the male-specific Cyp2d9 genes, respectively in females. In ER␣-deficient males, the Cyp2d9 gene continued to be expressed. Nuclear localization of Stat5b occurs in both sexes of ER␣-deficient mice, although it is normally observed in only wildtype males. Nuclear localization of Stat5b correlates with the repression of Cyp2a4 and expression of Cyp2d9, respectively. Because Stat5b was not detectable in liver nuclear extracts prepared from hypophysectomized ER␣-deficient females, the regulation by ER␣ appeared to be mediated through a pituitary hormone (i.e., growth hormone). Thus, ER␣ appears to play a key role in the mechanism that inhibits nuclear localization of Stat5b in female mice, leading to feminization of a ER␣-GHStat5b pathway and Cyp expression. Defaulting to this ER␣-dependent mechanism results in localization of Stat5b to nuclei, which masculinizes the expression of Cyp genes in male mice.Hepatic metabolism of steroids and xenochemicals is sexually dimorphic in rodents and other animals . Sex-specific metabolism is catalyzed by cytochrome P-450s (CYPs) that are expressed either in male or female animals. Certain metabolism by sex-specific CYPs may lead to sex-dependent susceptibility for chemical toxicity and carcinogenicity (Waxman and Chang, 1995a and references therein). Various molecular and/or cellular mechanisms that may regulate transcription of sex-specific CYP genes have been proposed: DNA methylation (Yokomori et al., 1995), hepatocyte nuclear factor 6 (Lahuna et al., 1997) and the Stat5b form of STAT (signal transducers and activators of transcription) (Subramanian et al., 1995;Udy et al., 1997;Teglund et al., 1998). However, defining the regulatory mechanism of sex-specific CYP expression remains to be a major interest in continuous investigations.Hormonally, growth hormone (GH) is known to play a central role in regulating sex-specific CYP genes. Gustafsson and Stenberg (1976) first suggested the existence of a pituitary factor that feminizes steroid metabolism by rat liver microsomes and called it "a feminization factor". Later, this pituitary factor was found to be GH (Kramer and Colby, 1976). 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). CYP2A4 and CYP2D9 are the well-characterized sex-specific mouse steroid hydroxylases; the former is the female-specific steroid 15␣-hydroxylase, whereas the latter is the male-specific steroid 16␣-hydroxylase Negishi, 1984a,b, 1988). Using GH-deficient Little mice, we previously showed that GH activates and...

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On the obligatory role of the hypophysis in sexual differentiation hepatic metabolism in rats.

Cited by 46 publications

References 24 publications

Diethylnitrosamine causes pituitary damage, disturbs hormone levels, and reduces sexual dimorphism of certain liver functions in the rat.

Diethylnitrosamine causes pituitary damage, disturbs hormone levels, and reduces sexual dimorphism of certain liver functions in the rat.

Effects of Hypophysectomy and Growth Hormone Treatment on Sex-Specific Forms of Cytochrome P-450 in Relation to Drug and Steroid Metabolisms in Rat Liver Microsomes

Developmental Action of Estrogen Receptor-α Feminizes the Growth Hormone-Stat5b Pathway and Expression ofCyp2a4andCyp2d9Genes in Mouse Liver

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