Molecular Evidence of Organic Ion Transporters in the Rat Adrenal Cortex with Adrenocorticotropin-Regulated Zonal Expression

Beéry, Erzsébet; Middel, Peter; Bahn, Andrew; Willenberg, Holger S.; Hagos, Yohannes; Koepsell, Hermann; Bornstein, S. R.; Müller, Gerhard A.; Burckhardt, Gerhard; Steffgen, Jürgen

doi:10.1210/en.2002-221001

Cited by 25 publications

(14 citation statements)

References 22 publications

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“…In 2003, rOat1 mRNA was detected in the outer zona fasciculata of the rat adrenal gland [133]. Furthermore, adrenocorticotropic hormone (ACTH) administration to rats increased rOat1 mRNA in the adrenal gland [133] and, consistent with this finding, hypophysectomy reduced adrenal gland rOat1 mRNA expression [133].…”

Section: Glucocorticoidsmentioning

confidence: 64%

“…These observations raised the question as to whether rOat1 is involved in the transport of corticosteroids out of the adrenal cortex. In support of this hypothesis, corticosterone was demonstrated to inhibit rOat1-mediated PAH uptake into expressing X. laevis oocytes [133]. These findings indicated that ACTHtriggered secretion of glucocorticoids from the adrenal cortex may depend on rOat1, which is possibly upregulated to facilitate the exit of glucocorticoids, however, rOat3 has not been assessed.…”

Section: Glucocorticoidsmentioning

confidence: 95%

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Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

VanWert

Gionfriddo

Sweet

2009

Biopharm & Drug Disp

219

238

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Our understanding of the mechanisms behind inter-and intra-patient variability in drug response is inadequate. Advances in the cytochrome P450 drug metabolizing enzyme field have been remarkable, but those in the drug transporter field have trailed behind. Currently, however, interest in carrier-mediated disposition of pharmacotherapeutics is on a substantial uprise. This is exemplified by the 2006 FDA guidance statement directed to the pharmaceutical industry. The guidance recommended that industry ascertain whether novel drug entities interact with transporters. This suggestion likely stems from the observation that several novel cloned transporters contribute significantly to the disposition of various approved drugs. Many drugs bear anionic functional groups, and thus interact with organic anion transporters (OATs). Collectively, these transporters are nearly ubiquitously expressed in barrier epithelia. Moreover, several reports indicate that OATs are subject to diverse forms of regulation, much like drug metabolizing enzymes and receptors. Thus, critical to furthering our understanding of patient-and condition-specific responses to pharmacotherapy is the complete characterization of OAT interactions with drugs and regulatory factors. This review provides the reader with a comprehensive account of the function and substrate profile of cloned OATs. In addition, a major focus of this review is on the regulation of OATs including the impact of transcriptional and epigenetic factors, phosphorylation, hormones and gender.

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Section: Glucocorticoidsmentioning

confidence: 64%

Section: Glucocorticoidsmentioning

confidence: 95%

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

VanWert

Gionfriddo

Sweet

2009

Biopharm & Drug Disp

219

238

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“…The release would not be rapidly controlled in such a mechanism and would continue constitutively. Recent in vitro studies (30) have demonstrated the intracellular retention of steroids against a concentration gradient at the plasma membrane. The last few years have witnessed the description of a steroid transport mechanism involving organic anion transport.…”

Section: Resultsmentioning

confidence: 99%

The rapid release of corticosterone from the adrenal induced by ACTH is mediated by nitric oxide acting by prostaglandin E ₂

Mohn

Fernández‐Solari

Laurentiis

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The adrenal cortex is a major stress organ in mammals that reacts rapidly to a multitude of external and internal stressors. Adrenocorticotropin (ACTH) is the main stimulator of the adrenal cortex, activating corticosteroid synthesis and secretion. We evaluated the mechanism of action of ACTH on adrenals of male rats, preserving the architecture of the gland in vitro. We demonstrated that both sodium nitroprusside (NP), a nitric oxide (NO) donor, and ACTH stimulate corticosterone release. NO mediated the acute response to ACTH because N-nitro-L-arginine methyl ester, a NO synthase inhibitor, and hemoglobin, a NO scavenger, blocked the stimulation of corticosterone release induced by ACTH. NP stimulated prostaglandin E release, which in turn stimulated corticosterone release from the adrenal. Additionally, indomethacin, which inhibits cyclooxygenase, and thereby, prostaglandin release, prevented corticosterone release from the adrenal induced by both NP and ACTH, demonstrating that prostaglandins mediate acute corticosterone release. Corticosterone content in adrenals after incubation with ACTH or NP was lower than in control glands, indicating that any de novo synthesis of corticosterone during this period was not sufficient to keep up with the release of the stored hormone. The release induced by ACTH or NP depleted the corticosterone content in the adrenal by Ϸ40% compared with the content of glands incubated in buffer. The mechanism of rapid release is as follows: NO produced by NO synthase activation by ACTH activates cyclooxygenase, which generates PGE 2, which in turn releases corticosterone stored in microvesicles and other organelles.cyclooxygenase ͉ indomethacin ͉ nitric oxide synthase ͉ N-nitro-L-arginine methyl ester

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“…In situ hybridizations and immunohistochemical analyses localized rat OAT1 to the zona fasciculata of the rat adrenal cortex, where cortisol synthesis and release take place. Importantly, OAT1 mRNA expression was strongly increased by treatment of rats with ACTH in vivo (2). Recently, we (1) reported a transporter protein-mediated translocation of cortisol in human (h)OAT3-expressing oocytes, and we also demonstrated probenecid-, cimetidine-, and glutarateinhibitable estrone sulfate (ES) uptake by forskolin-treated human adrenocortical cells (NCI-H295R).…”

mentioning

confidence: 88%

Regulation of steroid hormone biosynthesis enzymes and organic anion transporters by forskolin and DHEA-S treatment in adrenocortical cells

Asif

Ljubojević²,

Sabolić³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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. Regulation of steroid hormone biosynthesis enzymes and organic anion transporters by forskolin and DHEA-S treatment in adrenocortical cells. Am J Physiol Endocrinol Metab 291: E1351-E1359, 2006. First published July 11, 2006 doi:10.1152/ajpendo.00653.2005.-Several important physiological functions are regulated by cortisol. Previously, we demonstrated the involvement of human organic anion transporter 3 (hOAT3) in cortisol release. In the present study, we investigated the influence of dehydroepiandrosterone sulfate (DHEA-S) and estrone sulfate on cortisol release in a human adrenocortical cell line (NCI-H295R) compared with forskolin stimulation. Additionally, we examined the impact of forskolin and DHEA-S on the expression of key enzymes in steroid biosynthesis and expression of hOAT3 and -4 in NCI-H295R cells. The cortisol release was increased 10-fold after 24-h incubation with DHEA-S, but incubation with estrone sulfate did not show any significant change in cortisol release. When cells were incubated with DHEA-S in the presence of forskolin, an additive influence of DHEA-S stimulation of cortisol was recorded over forskolin alone. The 24-h stimulation of NCI-H295R cells with forskolin increased the expression of steroidogenic acute regulatory protein (StAR), CYP17, CYP21A2, and CYP11A1, whereas only StAR mRNA expression was increased significantly by incubation with DHEA-S. Immunofluorescence analyses revealed strongly elevated expression of hOAT3 by forskolin as well as by DHEA-S stimulation. We conclude that the increased cortisol release of adrenocortical cells by DHEA-S and forskolin stimulation is probably due to high expression of the key enzymes of steroid biosynthesis and hOAT3.cortisol; NCI-H295R cells; organic anion transporter 3; organic anion transporter 4; adrenal gland; human adrenocortical cells; SLC22A8; SLC22A11; forskolin; dehydroepiandrosterone sulfate THERE HAVE BEEN almost 50 different steroids recognized as adrenal cortex products, which cover a wide range of physiological activities. In most species, including the human, the physiologically most important corticosteroids are aldosterone, cortisol, and dehydroepiandrosterone sulfate (DHEA-S). The adrenal cortex also produces estrogen, progesterone, and a wide range of precursors and metabolites of these steroids. In the medulla, norepinephrine and epinephrine are major secretory products that are derivatives of the amino acid tyrosine.

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Molecular Evidence of Organic Ion Transporters in the Rat Adrenal Cortex with Adrenocorticotropin-Regulated Zonal Expression

Cited by 25 publications

References 22 publications

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

The rapid release of corticosterone from the adrenal induced by ACTH is mediated by nitric oxide acting by prostaglandin E ₂

Regulation of steroid hormone biosynthesis enzymes and organic anion transporters by forskolin and DHEA-S treatment in adrenocortical cells

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Molecular Evidence of Organic Ion Transporters in the Rat Adrenal Cortex with Adrenocorticotropin-Regulated Zonal Expression

Cited by 25 publications

References 22 publications

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

The rapid release of corticosterone from the adrenal induced by ACTH is mediated by nitric oxide acting by prostaglandin E 2

Regulation of steroid hormone biosynthesis enzymes and organic anion transporters by forskolin and DHEA-S treatment in adrenocortical cells

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The rapid release of corticosterone from the adrenal induced by ACTH is mediated by nitric oxide acting by prostaglandin E ₂