Overexpression of CYP3A aggravates endotoxin‐induced liver injury in hypophysectomized female rats

Takemura, Shigekazu; Minamiyama, Yukiko; Toyokuni, Shinya; Imaoka, Shingi; Hai, Seikan; Kubo, Shoji; Hirohashi, Kazuhiro; Funae, Yoshihiko; Okada, Shigeru

doi:10.1111/j.1872-034x.2007.00212.x

Cited by 4 publications

(6 citation statements)

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“…Cyclooxygenase 2 is also expressed by the endometrial tissues and cells, and PGE 2 or a cAMP analogue has been shown to induce StAR and aromatase expression and activity in the endometriotic stromal cells 5. We also found an elevated expression of CYP19A1, StAR, and COX-2 in EC as compared to EU and EN; however, their expression in EN compared to EU contrasted from previously reported studies 5,8,10,11,18,47,48. The most likely explanation for the difference could be the method of detection and primers used in these as compared to our study 48.…”

Section: Discussioncontrasting

confidence: 70%

“…Aromatase is expressed in a number of cells and tissues, and in the endometrium it is expressed by the stromal cells with elevated expression in EC endometrium. 5,[8][9][10] The expression of CYP19A1 in endometrial stromal cells (ESCs) is regulated by StAR, which has a rate-limiting regulatory function on steroid production in a number of cell types. 7,11 The expression of StAR is regulated by many factors, including luteinizing hormone (LH) receptor-activation of cyclic adenosine monophosphate (cAMP) and several cytokines and growth factors that are expressed by the endometriotic tissues.…”

Section: R E T R a C T E Dmentioning

confidence: 99%

“…The aromatase catalyzes the conversion of androstenedione to testosterone, which can be directly aromatized to 17β-estradiol (E 2 ). Aromatase is expressed in a number of cells and tissues, and in the endometrium it is expressed by the stromal cells with elevated expression in EC endometrium 5,8–10. The expression of CYP19A1 in endometrial stromal cells (ESCs) is regulated by StAR, which has a rate-limiting regulatory function on steroid production in a number of cell types 7,11.…”

Section: Introductionmentioning

confidence: 99%

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The Expression and Ovarian Steroid Regulation of Endometrial Micro-RNAs

Toloubeydokhti

Pan

et al. 2008

Reprod. Sci.

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MicroRNAs (miRNAs) which regulate gene expression stability displayed an aberrant expression profile in ectopic endometrium (ECE) as compared to eutopic (EUE) and normal endometrium (NE). We assessed the expression of miR-17-5p, miR-23a, miR-23b and miR-542-3p, their predicted target genes, steroidogenic acute regulatory protein, aromatase and cyclooxygenase-2, and influence of ovarian steroids on their expression in endometrial stromal (ESC) and glandular epithelial cells (GEC). The results indicated a lower expression of miR-23b and miR-542-3p and higher level of miR-17-5p in paired ECE and EUE as compared with NE. These levels were elevated and inversely correlated with the level of expression of their respective target genes in ECE. The expression of these miRNAs and genes was differentially regulated by 17β-estradiol, medroxyprogesterone acetate, ICI-182780 and RU-486, or their respective combinations in ESC and GEC. We concluded that altered expression of specific miRNAs in ECE, affecting the stability of their target genes expression, has direct implications in pathogenesis of endometriosis.

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Section: Discussioncontrasting

confidence: 70%

Section: R E T R a C T E Dmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Expression and Ovarian Steroid Regulation of Endometrial Micro-RNAs

Toloubeydokhti

Pan

et al. 2008

Reprod. Sci.

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“…This dosage of LPS was used in our previous studies 26 and by others. 27,28 At different time points (0, 2, 4, 8, and 12 h (n ¼ 7)), the animals were killed; blood and liver tissue were taken for analytical examination. All animals received humane care according to the criteria outlined in the 'Guide for the Care and Use of Laboratory Animals' prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication 86-23 revised 1985).…”

Section: Materials and Methods Endotoxic Shockmentioning

confidence: 99%

A novel endotoxin-induced pathway: upregulation of heme oxygenase 1, accumulation of free iron, and free iron-mediated mitochondrial dysfunction

Duvigneau

Piskernik

Haindl

et al. 2008

Laboratory Investigation

100

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Mitochondria are involved in the development of organ failure in critical care diseases. However, the mechanisms underlying mitochondrial dysfunction are not clear yet. Inducible hemoxygenase (HO-1), a member of the heat shock protein family, is upregulated in critical care diseases and considered to confer cytoprotection against oxidative stress. However, one of the products of HO-1 is Fe 2 þ which multiplies the damaging potential of reactive oxygen species catalyzing Fenton reaction. The aim of this study was to clarify the relevance of free iron metabolism to the oxidative damage of the liver in endotoxic shock and its impact on mitochondrial function. Endotoxic shock in rats was induced by injection of lipopolysaccharide (LPS) at a dose of 8 mg/kg (i.v.). We observed that the pro-inflammatory cytokine TNF-a and the liver necrosis marker aspartate aminotransferase were increased in blood, confirming inflammatory response to LPS and damage to liver tissue, respectively. The levels of free iron in the liver were significantly increased at 4 and 8 h after onset of endotoxic shock, which did not coincide with the decrease of transferrin iron levels in the blood, but rather with expression of the inducible form of heme oxygenase (HO-1). The proteins important for sequestering free iron (ferritin) and the export of iron out of the cells (ferroportin) were downregulated facilitating the accumulation of free iron in cells. The temporarily increased concentration of free iron in the liver correlated with the temporary impairment of both mitochondrial function and tissue ATP levels. Addition of exogenous iron ions to mitochondria isolated from control animals resulted in an impairment of mitochondrial respiration similar to that observed in endotoxic shock in vivo. Our data suggest that free iron released by HO-1 causes mitochondrial dysfunction in pathological situations accompanied by endotoxic shock.

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“…These two receptors mediate the effects of xenobiotics and therapeutic drugs on the regulation of CYP3A [ 18 ]. Sequence analysis showed that PXR and CAR are closely related to each other, and both require heterodimerization with RXR for high-affinity DNA binding [ 19 , 20 ], as shown in Figure 10 .…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Cytochrome P450 3A in Rat Liver by the Diorganotin (IV) Compound di-n-Butyl-di-(4-chlorobenzo-hydroxamato)tin (IV) and Its Probable Mechanism

Zhang

Liu

2012

Molecules

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The specific aims of this study were to evaluate the inhibition effect on CYP3A of di-n-butyl-di-(4-chlorobenzohydroxamato)tin (IV) (DBDCT), a tin-based complex with high antitumor activity, and the probable mechanism(s) of this action. Adult male SD rats were treated separately with natural saline (NS), lipopolysaccharide (LPS, 5 mg/kg), DBDCT (1.25, 2.5 and 5.0 mg/kg) intraperitoneally for 2 days after induction of CYP3A with dexamethasone (DEX, 100 mg/kg) for 4 days. Western blot analysis and fluorescent quantitation PCR (FQ-PCR) were conducted to determine the changes in expression of CYP3A, PXR, CAR and RXR. The biological accumulation of DBDCT and total Sn were determined by high-performance liquid chromatography (HPLC) and atomic fluorescence spectrometry (AFS). CYP450 content and CYP3A activities were significantly inhibited (p < 0.05) in DBDCT-treated rats compared with the control group, as was the expression of CYP3A (p < 0.05) at both protein and mRNA levels. In DBDCT-treated groups, the expression of PXR protein and mRNA increased, while the expression of CAR decreased. The biological accumulation of DBDCT and Sn in rat livers treated with DBDCT was high. The accumulation of DBDCT and Sn due to the inhibition of CYP3A may be involved in the mechanism of toxicity of DBDCT in rat liver.

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Overexpression of CYP3A aggravates endotoxin‐induced liver injury in hypophysectomized female rats

Abstract: Overexpression of CYP3A aggravated LPS-induced liver injury in rats, apparently through the formation of reactive oxygen species.

Cited by 4 publications

References 25 publications

The Expression and Ovarian Steroid Regulation of Endometrial Micro-RNAs

The Expression and Ovarian Steroid Regulation of Endometrial Micro-RNAs

A novel endotoxin-induced pathway: upregulation of heme oxygenase 1, accumulation of free iron, and free iron-mediated mitochondrial dysfunction

Inhibition of Cytochrome P450 3A in Rat Liver by the Diorganotin (IV) Compound di-n-Butyl-di-(4-chlorobenzo-hydroxamato)tin (IV) and Its Probable Mechanism

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