Regulation of the expression of two female-predominant CYP3A mRNAs (CYP3A41 and CYP3A44) in mouse liver by sex and growth hormones

Sakuma, Tsutomu; Endo, Yusuke; Mashino, Misae; Kuroiwa, Masami; Ôhara, Ayako; Jarukamjorn, Kanokwan; Nemoto, Nobuo

doi:10.1016/s0003-9861(02)00329-6

Cited by 73 publications

(84 citation statements)

References 23 publications

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“…Cyp3a11 encodes the most abundant CYP3A subfamily protein in the liver of male mice (Yanagimoto et al 1997) and the expression of this gene is sex-independent and GHindependent in males (Sakuma et al 2002;Jarukamjorn et al 2006). We showed previously that MC treatment caused a dramatic decrease in mouse hepatic CYP3A11 content, particularly at the protein level (Lee et al 2006).…”

Section: Constitutive Hepatic Cytochromes P450 and Pormentioning

confidence: 96%

Aryl hydrocarbon receptor-dependence of dioxin’s effects on constitutive mouse hepatic cytochromes P450 and growth hormone signaling components

Lee

Riddick

2012

Can. J. Physiol. Pharmacol.

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The aryl hydrocarbon receptor (AHR) has physiological roles in the absence of exposure to exogenous ligands and mediates adaptive and toxic responses to the environmental pollutant, 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD). A readily metabolized AHR agonist, 3-methylcholanthrene, disrupts expression of mouse hepatic growth hormone (GH) signaling components and suppresses cytochrome P450 2D9 (Cyp2d9), a male-specific gene controlled by pulsatile GH via signal transducer and activator of transcription 5b (STAT5b). Using TCDD as an essentially non-metabolized AHR agonist and Ahr −/− mice as the preferred model to determine the AHR-dependence of biological responses, we now show that two mouse hepatic STAT5b target genes, Cyp2d9 and major urinary protein 2 (Mup2), are suppressed by TCDD in an AHRdependent manner. TCDD also decreased hepatic mRNA levels for GH receptor, Janus kinase 2, and STAT5a/b with AHR-dependence. Without inducing selected hepatic inflammatory markers, TCDD caused AHR-dependent induction of Cyp1a1 and NADPH-cytochrome P450 oxidoreductase (Por) and suppression of Cyp3a11. In vehicle-treated mice, basal mRNA levels for CYP2D9, CYP3A11, POR, serum amyloid protein P, and MUP2 were influenced by Ahr genetic status. We conclude that AHR activation per se leads to dysregulation of hepatic GH signaling components and suppression of some, but not all, STAT5b target genes. Keywordsaryl hydrocarbon receptor; 2,3,7,8-tetrachlorodibenzo-p-dioxin; cytochrome P450; growth hormone receptor; Janus kinase 2; signal transducer and activator of transcription 5b; cytokineinducible Src homology 2 domain-containing protein; major urinary protein 2; inflammatory markers; NADPH-cytochrome P450 oxidoreductase

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Section: Constitutive Hepatic Cytochromes P450 and Pormentioning

confidence: 96%

Aryl hydrocarbon receptor-dependence of dioxin’s effects on constitutive mouse hepatic cytochromes P450 and growth hormone signaling components

Lee

Riddick

2012

Can. J. Physiol. Pharmacol.

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“…At that time, the effects of E2 and/or gonadectomy on sex-biased drug metabolism and thus on the sex-biased expression of cytochrome P450 (P450 CYP) enzymes were thought to be due solely to direct effects of sex steroid hormones on the hepatocyte (27,31). However, it was shown in 1973 by Colby et al (32), and extensively confirmed by numerous studies since then (27,(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43), that the feminizing effect on sex-biased liver gene expression of an injection of E2 into a rat or mouse was indirect and had an absolute dependence on the pituitary ( Figure 1). As explained in detail by Waxman and colleagues over the last 2 decades, this neuroendocrine mechanism of sex bias, working through an axis consisting of the hypothalamic arcuate nucleus-growth hormone releasing hormone (GHRH)-growth hormone (GH)-signal transducer and activator of transcription 5 (STAT5) accounts for sex-biased expression of >1,000 genes in the liver and also of body growth and body weight (27,(41)(42)(43)(44)(45)(46)(47)(48) (Figures 2, 3).…”

Section: A Gap In Knowledge In the Ph Literature Concerning Sex Bias mentioning

confidence: 79%

“…First, how does administration of exogenous E2 (or similar sex steroid) into an animal produce its effects? As mentioned earlier, it has been shown extensively that effects of exogenously injected E2 depend on generating the "feminine plasma growth hormone pattern" through central hypothalamic/pituitary mechanisms (27,(32)(33)(34)(35)(36)(37)(38)(39)(40) (Figure 1). Specifically, a single injection of E2 into a rodent affects the function of cells in the arcuate and ventromedial nucleus in the hypothalamus and additional nuclei therein (27,(49)(50)(51)(52)(53)(54).…”

Section: The Hypothalamic (Ghrh)-pituitary (Gh)-distal Tissues (Stat5mentioning

confidence: 87%

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

Sehgal

Yang

Miller

2015

Mol Med

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Pulmonary hypertension (PH) is a disease with high morbidity and mortality. The prevalence of idiopathic pulmonary arterial hypertension (IPAH) and hereditary pulmonary arterial hypertension (HPAH) is approximately two-to four-fold higher in women than in men. Paradoxically, there is an opposite male bias in typical rodent models of PH (chronic hypoxia or monocrotaline); in these models, administration of estrogenic compounds (for example, estradiol-17β [E2]) is protective. Further complexities are observed in humans ingesting anorexigens (female bias) and in rodent models, such as after hypoxia plus SU5416/Sugen (little sex bias) or involving serotonin transporter overexpression or dexfenfluramine administration (female bias). These complexities in sex bias in PH remain incompletely understood. We recently discovered that conditional deletion of signal transducer and activator of transcription 5a/b (STAT5a/b) in vascular smooth muscle cells abrogated the male bias in PH in hypoxic mice and that late-stage obliterative lesions in patients of both sexes with IPAH and HPAH showed reduced STAT5a/b, reduced Tyr-P-STAT5 and reduced B-cell lymphoma 6 protein (BCL6). In trying to understand the significance of these observations, we realized that there existed a wellcharacterized E2-sensitive central neuroendocrine mechanism of sex bias, studied over the last 40 years, that, at its peripheral end, culminated in species-specific male ("pulsatile") versus female ("more continuous") temporal patterns of circulating growth hormone (GH) levels leading to male versus female patterned activation of STAT5a/b in peripheral tissues and thus sex-biased expression of hundreds of genes. In this report, we consider the contribution of this neuroendocrine mechanism (hypothalamus-GH-STAT5) in the generation of sex bias in different PH situations.

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“…This has since been extensively confirmed -the feminizing effects of exogenously administered E2 or the masculinizing effects of testosterone on sex-biased gene expression in the liver are blocked by hypophysectomy. 29,[38][39][40][41][42][43][44][45][46][47][48] The major target of injected E2 (and other sex hormones) is the hypothalamus, in particular the arcuate nucleus. [49][50][51][52][53][54] [Note that there is no blood-brain barrier at the arcuate nucleus and additional "circumventricular" regions in the brain.]…”

mentioning

confidence: 99%

STAT5a/b contribute to sex bias in vascular disease: A neuroendocrine perspective

et al. 2015

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ABSTRACT. Previous studies have elucidated a neuroendocrine mechanism consisting of the hypothalamus (growth hormone releasing hormone, GHRH) -pituitary (growth hormone, GH) -STAT5a/b axis that underlies sex-biased gene expression in the liver. It is now established that male vs female patterned secretion of GHRH, and thus of circulating GH levels ("pulsatile" vs "more continuous" respectively), leading to differently patterned activation of PY-STAT5a/b in hepatocytes results in sex-biased gene expression of cohorts of hundreds of downstream genes. This review outlines new data in support of a STAT5a/b-based mechanism of sex bias in the vascular disease pulmonary hypertension (PH). Puzzling observations in PH include its 2-4-fold higher prevalence in women but a male-dominance in many rodent models, and, paradoxically, inhibition of PH development by estrogens in such models. We observed that conditional deletion of STAT5a/b in vascular smooth muscle cells (SMC) in mice converted the male-dominant model of chronic hypoxia-induced PH into a female-dominant phenotype. In human idiopathic PH, there was reduced STAT5a/b and PY-STAT5 in cells in late-stage obliterative pulmonary arterial lesions in both men and women. A juxtaposition of the prior liver data with the newer PH-related data drew attention to the hypothalamus-GH-STAT5 axis, which is the major target of estrogens at the level of the hypothalamus. This hypothesis explains many of the puzzling aspects of sex bias in PH in humans and rodent models. The extension of STAT5-anchored mechanisms of sex bias to vascular disease emphasizes the contribution of central neuroendocrine processes in generating sexual dimorphism in different tissues and cell types.

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Regulation of the expression of two female-predominant CYP3A mRNAs (CYP3A41 and CYP3A44) in mouse liver by sex and growth hormones

Cited by 73 publications

References 23 publications

Aryl hydrocarbon receptor-dependence of dioxin’s effects on constitutive mouse hepatic cytochromes P450 and growth hormone signaling components

Aryl hydrocarbon receptor-dependence of dioxin’s effects on constitutive mouse hepatic cytochromes P450 and growth hormone signaling components

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

STAT5a/b contribute to sex bias in vascular disease: A neuroendocrine perspective

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