Cytoprotective actions of estrogens against tert-butyl hydroperoxide-induced toxicity in hepatocytes

Leal, Ana M.; Ruiz‐Larrea, M. Begoña; Martı́nez, Rosa; Lacort, Mercedes

doi:10.1016/s0006-2952(98)00248-2

Cited by 43 publications

(25 citation statements)

References 31 publications

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“…The concentrations required for a significant antioxidative protection of ·-MG uptake in our in vitro system are higher than the estradiol-17ß levels that occur naturally in vivo but are consistent with those that have been previously shown to have antioxidant activity in different cellular and cell-free systems [28]. In rat hepatocyte incubated with t-BHP [29], a high concentration of estrogens (10-200 ÌM) exhibited a protective effect. It is unlikely that this mechanism is solely responsible for the protection effect of the estradiol-17ß, considering plasma concentrations of estradiol-17ß are in the nanomolar range, depending on sex and menopausal status [30].…”

Section: Discussionsupporting

confidence: 87%

Effects of Sex Hormones on Na<sup>+</sup>/Glucose Cotransporter of Renal Proximal Tubular Cells following Oxidant Injury

Han

Park

et al. 2001

Kidney Blood Press Res

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It was reported that reactive oxygen metabolites play an important role in the pathogenesis of several renal diseases including glomerulonephritis, ischemia and acute tubular necrosis. However, the effect of oxidants and protective effect of sex steroid hormones on Na⁺/glucose cotransporter of renal proximal tubular cells is not yet elucidated. In the present study, we examined the effect of sex steroid hormones against tert-butyl hydroperoxide (t-BHP)-induced alteration of Na⁺/glucose cotransporter activity in primary cultured rabbit renal proximal tubule cells (PTCs). t-BHP inhibited α-methyl-D-glucopyranoside (α-MG) uptake in a dose-dependent manner. t-BHP-induced inhibition of α-MG uptake was due not to K_m but to the decrease of V_max. 0.5 mM t-BHP-induced inhibition of α-MG uptake was significantly blocked by estradiol-17β, but not by progesterone and testosterone. This protective effect was not blocked by estrogen receptor antagonist or transcription and translation inhibitor. In addition, 0.5 mM t-BHP increased [³H]-arachidonic acid (AA) release and Ca²⁺ uptake. These effects of t-BHP were also significantly blocked by estradiol-17β, but not by progesterone and testosterone. Protective efficacy of estradiol-17β on t-BHP-induced inhibition of α-MG uptake is exhibited between antioxidants and iron chelators. In conclusion, estradiol-17β, but not progesterone and testosterone, partially prevented t-BHP-induced inhibition of α-MG uptake through its antioxidant activity dependent upon phenol structures and inhibition of AA release and Ca²⁺ influx.

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Section: Discussionsupporting

confidence: 87%

Effects of Sex Hormones on Na<sup>+</sup>/Glucose Cotransporter of Renal Proximal Tubular Cells following Oxidant Injury

Han

Park

et al. 2001

Kidney Blood Press Res

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“…Although estrogen can act as an antioxidant, this effect generally occurs at fairly high concentrations in vitro (Leal et al, 1998;Prokai et al, 2003). Nevertheless, the contribution of an antioxidant effect of estrogen to the presently reported findings cannot be excluded.…”

mentioning

confidence: 61%

Gender Differences in the Endotoxin-Induced Inflammatory and Vascular Responses: Potential Role of Poly(ADP-ribose) Polymerase Activation

Mabley

Horváth

Murthy

et al. 2005

J Pharmacol Exp Ther

115

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Activation of poly(ADP-ribose) polymerase (PARP) is an important factor in the pathogenesis of various cardiovascular and inflammatory diseases. Here, we report that the gender-specific inflammatory response is preferentially down-regulated by PARP in male animals. Female mice produce less tumor necrosis factor-␣ and macrophage inflammatory protein-1␣ in response to systemic inflammation induced by endotoxin than male mice and are resistant to endotoxin-induced mortality. Pharmacological inhibition of PARP is effective in reducing inflammatory mediator production and mortality in male, but not in female, mice. Ovariectomy partially reverses the protection seen in female mice. Endotoxin-induced PARP activation in circulating leukocytes is reduced in male, but not female, animals by pharmacological PARP inhibition, as shown by flow cytometry. Pretreatment of male mice with 17-␤-estradiol prevents endotoxin-induced hepatic injury and reduces poly(ADPribosyl)ation in vivo. In male, but not female, animals, endotoxin induces an impairment of the endothelium-dependent relaxant responses, which is prevented by PARP inhibition. In vitro oxidant-induced PARP activation is reduced in cultured cells placed in female rat serum compared with male serum. Estrogen does not directly inhibit the enzymatic activity of PARP in vitro. However, PARP and estrogen receptor ␣ form a complex, which binds to DNA in vitro, and the DNA binding of this complex is enhanced by estrogen. Thus, estrogen may anchor PARP to estrogen receptor ␣ and to the DNA and prevent its recognition of DNA strand breaks and hence its activation. In conclusion, the gender difference in the inflammatory response shows preferential modulation by PARP in male animals.

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“…17␤-estradiol also protects liver and isolated hepatocytes under pathophysiological conditions associated with a rise in [Ca 2ϩ ] c (90 -93) through an unknown mechanism that appears to be unrelated to classical ER activation (91,92). Our finding that 17␤-estradiol can also, like ANP, stimulate Ca 2ϩ efflux through particulate guanylyl cyclase activation and attenuate [Ca 2ϩ ] c elevations suggests that such a cytoprotective mechanism may underlie 17␤-estradiol-mediated hepatoprotection and may, thus, prove to be of more widespread physiological significance.…”

Section: Discussionmentioning

confidence: 99%

17β-Estradiol Elevates cGMP and, via Plasma Membrane Recruitment of Protein Kinase GIα, Stimulates Ca2+ Efflux from Rat Hepatocytes

Stratton

Squires

Green

2010

Journal of Biological Chemistry

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Rapid non-genomic effects of 17␤-estradiol, the principal circulating estrogen, have been observed in a wide variety of cell types. Here we investigate rapid signaling effects of 17␤-estradiol in rat hepatocytes. We show that, above a threshold concentration of 1 nM, 17␤-estradiol, but not 17␣-estradiol, stimulates particulate guanylyl cyclase to elevate cGMP, which through activation and plasma membrane recruitment of protein kinase G isoform I␣, stimulates plasma membrane Ca 2؉ -ATPase-mediated Ca 2؉ efflux from rat hepatocytes. These effects are extremely rapid in onset and are mimicked by a membrane-impermeant 17␤-estradiol-BSA conjugate, suggesting that 17␤-estradiol acts at the extracellular face of the plasma membrane. We also show that 17␤-estradiol binds specifically to the intact hepatocyte plasma membrane through an interaction that is competed by an excess of atrial natriuretic peptide but also shows many similarities to the pharmacological characteristics of the putative ␥-adrenergic receptor. We, therefore, propose that the observed rapid signaling effects of 17␤-estradiol are mediated either through the guanylyl cyclase A receptor for atrial natriuretic peptide or through the ␥-adrenergic receptor, which is either itself a transmembrane guanylyl cyclase or activates a transmembrane guanylyl cyclase through cross-talk signaling.

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Cytoprotective actions of estrogens against tert-butyl hydroperoxide-induced toxicity in hepatocytes

Cited by 43 publications

References 31 publications

Effects of Sex Hormones on Na<sup>+</sup>/Glucose Cotransporter of Renal Proximal Tubular Cells following Oxidant Injury

Effects of Sex Hormones on Na<sup>+</sup>/Glucose Cotransporter of Renal Proximal Tubular Cells following Oxidant Injury

Gender Differences in the Endotoxin-Induced Inflammatory and Vascular Responses: Potential Role of Poly(ADP-ribose) Polymerase Activation

17β-Estradiol Elevates cGMP and, via Plasma Membrane Recruitment of Protein Kinase GIα, Stimulates Ca2+ Efflux from Rat Hepatocytes

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