Diagnosis of intrauterine fetal growth retardation by prolongation of dehydroepiandrosterone sulfate (DHAS) half-life after DHAS loading

Rabe, T.; Runnebaum, B.; Koeppen, U.; Widmaier, G; Kubli, F.

doi:10.1016/0028-2243(82)90025-9

Cited by 11 publications

(7 citation statements)

References 27 publications

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“…When fetal adrenals are stimulated by ACTH in the second trimester, synthesis of DHEA-s increases. Accumulation of excess DHEA-s is associated with intrauterine growth retardation (61 ), possibly because of inhibition of cell proliferation and differentiation by DHEA-s (62). If the rise in DHEA-s stimulates extrahepatic expression of CYP3A7 in the second trimester, this enzyme could provide additional protection for the fetus by forming the nontoxic 1 6-a-hydroxylated DHEA-s metabolite.…”

Section: Discussionmentioning

confidence: 99%

Identification of the fetal liver cytochrome CYP3A7 in human endometrium and placenta.

Schuetz¹,

Kauma²,

Guzelian³

1993

J. Clin. Invest.

104

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Placenta and endometrium carry out steroidogenic biotransformation reactions such as 6-ft-hydroxylation of cortisol, a reaction characteristic of the dominant family of cytochromes P450 in human liver, CYP3A. To investigate the possible role in these extrahepatic tissues of the CYP3A microsomal hemoproteins, we analyzed placental and endometrial microsomes on Western blots developed with an anti-human CYP3A antibody. We found an immunoreactive 51,500 D protein that migrated between CYP3A3 (HLp) and CYP3A5 (HLp2) identical with CYP3A7 (HFLa). CYP3A7, a form found prominently in human fetal liver microsomes, was first isolated as a liver 16-adehydroepiandrosterone-sulfate hydroxylase. Northern blot analysis of total RNA isolated from placenta or from endometrium demonstrated a single band that cross-hybridized with a CYP3A7 cDNA. Amplification of the same RNA samples with the use of primers specific for CYP3A7, produced a 552-bp segment that had the predicted size and the same DNA sequence as does liver CYP3A7 cDNA. Hybridizable endometrial CYP3A7 mRNA was detected more frequently (six of seven samples) and in higher amounts (-12-fold higher) in pregnant compared with nonpregnant women (4 of 12 samples). In addition, during the secretory phase of the menstrual cycle CYP3A7 expression was sixfold higher than in the one sample from the proliferative phase that had detectable CYP3A7 mRNA. Moreover, the amounts of placental and endometrial CYP3A7 mRNA and protein increased substantially from the first to the second trimester of pregnancy. We conclude that placenta and endometrium express the same P450 as is found in fetal liver. These tissues represent a previously unrecognized and quantitatively important site for 6-ft-hydroxylation and 16-a-hydroxylation of specific steroid precursors, possibly for protection of the fetus from the toxic effects of endogenous steroids and foreign substrates. (J. Clin. Invest. 1993.

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Section: Discussionmentioning

confidence: 99%

Identification of the fetal liver cytochrome CYP3A7 in human endometrium and placenta.

Schuetz¹,

Kauma²,

Guzelian³

1993

J. Clin. Invest.

104

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“…Accumulation of excess DHEAS is associated with intrauterine growth retardation (IUGR) (9). DHEAS is an OAT4 substrate.…”

Section: Introductionmentioning

confidence: 99%

Comparison of the Interaction of Human Organic Anion Transporter hOAT4 with PDZ Proteins between Kidney Cells and Placental Cells

Zhou

Tanaka

et al. 2007

Pharm Res

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“…It is believed that estrogen biosynthesis in the placenta uses dehydroepiandrosterone sulfate (DHEAS), a precursor produced in large amount by the fetal adrenals. Accumulation of excess DHEAS is associated with intrauterine growth retardation (17). DHEAS is an OAT4 substrate.…”

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confidence: 99%

Regulation of human organic anion transporter 4 by progesterone and protein kinase C in human placental BeWo cells

Zhou¹,

You²

2007

American Journal of Physiology-Endocrinology and Metabolism

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Human organic anion transporter 4 (hOAT4) belongs to a family of organic anion transporters that play critical roles in the body disposition of clinically important drugs, including anti-human immunodeficiency virus therapeutics, anti-tumor drugs, antibiotics, antihypertensives, and anti-inflammatories. hOAT4 is abundantly expressed in the placenta. In the current study, we examined the regulation of hOAT4 by pregnancy-specific hormones progesterone (P4) and 17␤-estradiol (E2) and by protein kinase C (PKC) in human placental BeWo cells. P4 induced a time-and concentration-dependent downregulation of hOAT4 transport activity, whereas E2 had no effect on hOAT4 function. The downregulation of hOAT4 activity by P4 mainly resulted from a decreased cell surface expression without a change in total cell expression of the transporter, kinetically revealed as a decreased Vmax without significant change in Km. Activation of PKC by phorbol 12,13-dibutyrate also resulted in an inhibition of hOAT4 activity through a decreased cell surface expression of the transporter. However, P4-induced downregulation of hOAT4 activity could not be prevented by treating hOAT4-expressing cells with the PKC inhibitor staurosporine. We concluded that both P4 and activation of PKC inhibited hOAT4 activity through redistribution of the transporter from cell surface to the intracellular compartments. However, P4 regulates hOAT4 activity by mechanisms independent of PKC pathway. acute regulation HUMAN ORGANIC ANION TRANSPORTER 4 (hOAT4) belongs to a family of organic anion transporters that play critical roles in the body disposition of clinically important drugs, including anti-human immunodeficiency virus therapeutics, anti-tumor drugs, antibiotics, antihypertensives, and anti-inflammatories (3,7,18,19,24). hOAT4 is abundantly expressed in the kidney and placenta (4). In the kidney, OAT4 functions as an organic anion/dicarboxylate exchanger at the apical membrane of the proximal tubule and is responsible for the reabsorption of organic anions driven by an outwardly directed dicarboxylate gradient (6). In the placenta, hOAT4 is localized to the basolateral membrane of syncytiotrophoblasts (20). It is believed that estrogen biosynthesis in the placenta uses dehydroepiandrosterone sulfate (DHEAS), a precursor produced in large amount by the fetal adrenals. Accumulation of excess DHEAS is associated with intrauterine growth retardation (17). DHEAS is an OAT4 substrate. Therefore, OAT4 may play an important role in efficient uptake of DHEAS by the placenta for the production of estrogens and for the protection of fetus from the cytotoxicity of DHEAS.Computer modeling has shown that hOAT4 contains multiple potential glycosylation sites in its first extracellular loop. The glycosylation process occurs in two major steps: the first step is the addition of oligosaccharides to the nascent protein, and the second step is the processing of added oligosaccharides during which the added oligosaccharides are modified and trimmed. Our group (27) previously sho...

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Diagnosis of intrauterine fetal growth retardation by prolongation of dehydroepiandrosterone sulfate (DHAS) half-life after DHAS loading

Cited by 11 publications

References 27 publications

Identification of the fetal liver cytochrome CYP3A7 in human endometrium and placenta.

Identification of the fetal liver cytochrome CYP3A7 in human endometrium and placenta.

Comparison of the Interaction of Human Organic Anion Transporter hOAT4 with PDZ Proteins between Kidney Cells and Placental Cells

Regulation of human organic anion transporter 4 by progesterone and protein kinase C in human placental BeWo cells

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