Identification of a cytochrome P-450 in human fetal liver related to glucocorticoid-inducible cytochrome P-450HLp in the adult

Wrighton, Steven; Molowa, David T.; Guzelian, Philip S.

doi:10.1016/0006-2952(88)90299-7

Cited by 59 publications

(33 citation statements)

References 10 publications

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“…Indeed, consistent with previous studies in vivo (Heuman et al, 1982;Wrighton et al, 1985;Baldwin et al, 2006) and in vitro (Kocarek et al, 1995;Meredith et al, 2003), a marked increase was …”

Section: Discussionsupporting

confidence: 91%

Liverbeads: A Practical and Relevant In Vitro Model for Gene Induction Investigations

Khansa¹,

Blanck²,

Bars³

2010

Drug Metab Dispos

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ABSTRACT:Cryopreserved rat hepatocytes entrapped within an alginate matrix, commercially available as Liverbeads, were evaluated for their relevance as a screening tool for gene induction in vitro, using quantitative real-time reverse transcriptase-polymerase chain reaction. They were treated with the reference compounds ␤-naphthoflavone (BNF), phenobarbital (PB), pregnenolone 16␣-carbonitrile (PCN), and clofibric acid (CLO) and analyzed for mRNA levels of Cyp1a1, Cyp2b1, Cyp3a1, Cyp4a1, Ugt1a6, and Ugt2b1. In addition, for PB and PCN, the results were compared with those obtained in rat liver in vivo. For each inducer, the gene induction profiles obtained with the Liverbeads in vitro model were time-and dose-dependent. The in vitro gene expression profiles confirmed the corresponding known P450 and UGT induction by each reference compound.

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Section: Discussionsupporting

confidence: 91%

Liverbeads: A Practical and Relevant In Vitro Model for Gene Induction Investigations

Khansa¹,

Blanck²,

Bars³

2010

Drug Metab Dispos

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“…Microsomes were prepared and stored as previously described ( 18,30,31 ). Protein concentration was determined colorimetrically as previously described ( 18,30,31 (33). Positive phage were rescreened by use of this probe.…”

Section: Methodsmentioning

confidence: 99%

“…In contrast, the 16-a-hydroxylated form of DHEA-s does not inhibit progesterone biosynthesis ( 17) and may be less toxic to the fetus. Recently, a form of cytochrome P450 termed HFLa (CYP3A7) that has been thought to be expressed in fetal liver exclusively (18)(19)(20)(21)(22)(23)(24)(25) was found to catalyze 16-a-hydroxylation of DHEA-s (23). One interpretation of this finding might be that 16-a-hydroxylation of DHEA-s serves a self protective fetal function confined to the developing liver.…”

Section: Introductionmentioning

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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“…DEX induces cytochrome P450 (P450) genes, such as Cyp3a11 and Cyp2b10 in mice and CYP3A4 in humans Wrighton et al, 1985;Strom et al, 1996;Yanagimoto et al, 1997). The mechanism of this induction is complex and is mediated by a number of nuclear receptors.…”

Section: Introductionmentioning

confidence: 99%

In Vivo Responses of the Human and Murine Pregnane X Receptor to Dexamethasone in Mice

Scheer¹,

Ross²,

Kapelyukh³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Dexamethasone (DEX) is a potent and widely used anti-inflammatory and immunosuppressant glucocorticoid. It can bind and activate the pregnane X receptor (PXR), which plays a critical role as xenobiotic sensor in mammals to induce the expression of many enzymes, including cytochromes P450 in the CYP3A family. This induction results in its own metabolism. We have used a series of transgenic mouse lines, including a novel, improved humanized PXR line, to compare the induction profile of PXR-regulated drugmetabolizing enzymes after DEX administration, as well as looking at hepatic responses to rifampicin (RIF). The new humanized PXR model has uncovered further intriguing differences between the human and mouse receptors in that RIF only induced Cyp2b10 in the new humanized model. DEX was found to be a much more potent inducer of Cyp3a proteins in wild-type mice than in mice humanized for PXR. To assess whether PXR is involved in the detoxification of DEX in the liver, we analyzed the consequences of high doses of the glucocorticoid on hepatotoxicity on different PXR genetic backgrounds. We also studied these effects in an additional mouse model in which functional mouse Cyp3a genes have been deleted. These strains exhibited different sensitivities to DEX, indicating a protective role of the PXR and CYP3A proteins against the hepatotoxicity of this compound.Dexamethasone (DEX) is a synthetic glucocorticoid that is used to treat a wide variety of medical conditions. It is a potent anti-inflammatory and immunosuppressant, which is metabolized primarily by the liver and undergoes renal excretion (Minagawa et al., 1986).DEX induces cytochrome P450 (P450) genes, such as Cyp3a11 and Cyp2b10 in mice and CYP3A4 in humans Wrighton et al., 1985;Strom et al., 1996;Yanagimoto et al., 1997). The mechanism of this induction is complex and is mediated by a number of nuclear receptors. For example, the glucocorticoid receptor (GR) is essential for the DEX-mediated induction of Cyp2b proteins in mouse liver, but at high doses the induction of Cyp3a enzymes is mediated by other transcription factors (Schuetz et al., 2000). In addition, it has been reported that DEX induction of CYP3A4 in human hepatocytes is mediated by several transcription factors (Pascussi et al., 2001). At low (nanomolar) concentrations, CYP3A4 induction is mediated by a GR-dependent elevation of pregnane X receptor (PXR) expression, whereas at high (supramicromolar) concentrations, DEX directly binds to and activates PXR. In addition, submicromolar concentrations of DEX also enhance the expression of the constitutive androstane receptor (CAR) and the retinoid X receptor-␣ in human hepatocytes (Pascussi et al., 2000a,b). It has been shown that DEX is a more potent ligand for mouse PXR than the human receptor (Meehan et al., 1988;Moore et al., 2000), and hepatic induction of Cyp3a, but not Cyp2b, expression in mice is PXRdependent (Schuetz et al., 2000;Scheer et al., 2008).CYP3A plays a central role in DEX disposition in human liver because it catalyzes th...

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Identification of a cytochrome P-450 in human fetal liver related to glucocorticoid-inducible cytochrome P-450HLp in the adult

Cited by 59 publications

References 10 publications

Liverbeads: A Practical and Relevant In Vitro Model for Gene Induction Investigations

Liverbeads: A Practical and Relevant In Vitro Model for Gene Induction Investigations

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

In Vivo Responses of the Human and Murine Pregnane X Receptor to Dexamethasone in Mice

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