The Fetal Specific GeneCYP3A7Is Inducible by Rifampicin in Adult Human Hepatocytes in Primary Culture

Greuet, Joëlle; Pichard, Lydiane; Bonfils, Claude; Domergue, J; Maurel, Patrick

doi:10.1006/bbrc.1996.1231

Cited by 52 publications

(25 citation statements)

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“…In the case of CYP3A5, all these samples are heterozygous for the CYP3A5*1A allele, which has been linked to the increased expression of the CYP3A5 protein Kuehl et al, 2001). The expression of CYP3A7 was originally thought to be restricted to fetal livers (Wrighton et al, 1988), but its detection in adult livers in this study is in agreement with more recent reports (Schuetz et al, 1994;Greuet et al, 1996;Pascussi et al, 1999;Tateishi et al, 1999). CYP3A7 gene transcripts reach one-fifth of the combined CYP3A transcript pool, but in most samples their contribution remains low.…”

Section: Discussionsupporting

confidence: 92%

“…The third CYP3A, CYP3A7, was originally described in the human fetal liver where it accounts for about 50% of the total P450 protein (Wrighton et al, 1988). More recent reports suggest constitutive or induced expression of CYP3A7 in adult human livers (Schuetz et al, 1994;Greuet et al, 1996;Pascussi et al, 1999;Tateishi et al, 1999), but a final verdict has been hampered by the lack of specific antibodies. Similarly, no protein expression data are available for the recently identified fourth member of the family, CYP3A43 (Domanski et al, 2001b;Gellner et al, 2001;Westlind et al, 2001).…”

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confidence: 99%

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Interindividual Variability and Tissue-Specificity in the Expression of Cytochrome P450 3A mRNA

Koch¹,

Weil²,

Wolbold³

et al. 2002

Drug Metab Dispos

279

188

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ABSTRACT:The elucidation of the individual contributions of the four CYP3A genes to the overall CYP3A activity has been hampered by similarities in their sequence and function. We investigated the expression of CYP3A mRNA species in the liver and in various other tissues using gene-specific TaqMan probes. CYP3A4 transcripts were the most abundant CYP3A mRNA in each of the 63 white European livers tested and accounted on average for 95% of the combined CYP3A mRNA pool. CYP3A5 and CYP3A7 each contributed on average 2%, whereas CYP3A43 contributed 0.3% transcripts to this pool. Fourteen percent of livers exhibited an increased share of CYP3A5 transcripts (range 4-20%). These livers were either heterozygous for the marker of the CYP3A5 polymorphism, the CYP3A5*1A allele, or expressed very low levels of CYP3A4 mRNA. The CYP3A7 expression was bimodal, and it was increased in 15% livers. CYP3A4 was the dominant CYP3A in the intestine, followed by CYP3A5. CYP3A5 and CYP3A7, but not CYP3A4, were also expressed in the adrenal gland and in the prostate, whereas only CYP3A5 was detected in the kidney. These three tissues were shown to express much lower levels of pregnane X receptor mRNA than the intestine, indicating possibly a different mode of regulation of CYP3A expression. Expression of CYP3A genes was undetectable in peripheral blood lymphocytes. In summary, these assays and results should aid in our efforts to further dissect the regulation and the physiological and pharmacological significance of CYP3A isozymes.

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

Interindividual Variability and Tissue-Specificity in the Expression of Cytochrome P450 3A mRNA

Koch¹,

Weil²,

Wolbold³

et al. 2002

Drug Metab Dispos

279

188

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“…In contrast to CYP3A5, CYP3A7 contains a PXR binding element in the 5Ј promoter regions of the gene and has been reported to be inducible by rifampin in primary human hepatocytes (Greuet et al, 1996). In the current study, a significant increase in the number of individuals expressing lymphocytic CYP3A7 mRNA was noted in response to rifampin treatment (24 versus 54%).…”

Section: Discussionmentioning

confidence: 42%

Induction of Multidrug Resistance-1 and Cytochrome P450 mRNAs in Human Mononuclear Cells by Rifampin

Asghar

Gorski²,

Haehner‐Daniels³

et al. 2002

Drug Metab Dispos

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This paper is available online at http://dmd.aspetjournals.org ABSTRACT:Reverse transcription-polymerase chain reaction (RT-PCR) and quantitative, competitive RT-PCR were used to examine the capability of rifampin to induce the expression of mRNA derived from multidrug resistance-1 (MDR1) and drug-metabolizing cytochrome P450 (P450) genes in the mononuclear fraction (lymphocytes) of human blood. A total of 50 healthy volunteers (age, 18-74) participated in two studies in which 600 mg of rifampin was administered orally once daily in the evening for 7 days. Twenty of these individuals also received fexofenadine before and after rifampin dosing. MDR1 and CYP2C8 mRNAs were expressed in 100% (50 of 50) and 95% (35 of 37) of individuals, respectively, at baseline. A significant (P < 0.05; n ‫؍‬ 37) increase in the expression of MDR1 mRNA from 176,900 ؎ 122,000 to 248,500 ؎ 162,300 molecules/g of RNA was observed following rifampin administration in the human lymphocytes. There was no significant (P > 0.05) difference in MDR1 mRNA expression between males and females at baseline. Interestingly, 58% of the individuals (n ‫؍‬ 29) demonstrated a 120% increase [95% confidence interval (CI); 120%; range, 81-153%; responders] in MDR1 mRNA expression. In contrast, the remaining 42% of individuals (n ‫؍‬ 21) exhibited a mean decrease of ؊5.2% (95% CI; ؊5.2%; range, ؊15 to ؉4%; nonresponders). Rifampin steady-state trough serum concentrations were not significantly different (P > 0.05) between responders and nonresponders. Likewise, there was no relationship between the observed induction in MDR1 mRNA expression in lymphocytes and the observed increase in fexofenadine oral clearance in twenty volunteers. The mRNA of CYP2E1, CYP3A5, CYP3A7, CYP4A11, and CYP4B1 genes were variably expressed at baseline and following rifampin treatment. In contrast, CYP2C9 and CYP3A4 mRNAs were undetectable in lymphocytes both before and after rifampin dosing. Interindividual variability in baseline expression and inducibility of MDR1 and P450 mRNA in human lymphocytes appeared to be substantial and may not reflect the expression of these enzymes in other tissues.

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“…Total RNA (30 g) was analyzed by the RNase protection assay with specific riboprobe as previously described (Greuet et al, 1996) with minor modification. Total RNA was hybridized with radiolabeled antisense RNA probe (100,000 to 150,000 cpm) overnight at 42°C after incubation for 10 min at 95°C.…”

Section: Methodsmentioning

confidence: 99%

Dexamethasone Induces Pregnane X Receptor and Retinoid X Receptor-α Expression in Human Hepatocytes: Synergistic Increase of CYP3A4 Induction by Pregnane X Receptor Activators

et al. 2000

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In this report we show that submicromolar concentrations of dexamethasone enhance pregnane X receptor (PXR) activatormediated CYP3A4 gene expression in cultured human hepatocytes. Because this result is only observed after 24 h of cotreatment and is inhibited by pretreatment with cycloheximide, we further investigated which factor(s), induced by dexamethasone, might be responsible for this effect. We report that dexamethasone increases both retinoid X receptor-␣ (RXR␣) and PXR mRNA expression in cultured human hepatocytes, whereas PXR activators such as rifampicin and clotrimazole do not. Accumulation of RXR␣ and PXR mRNA reaches a maximum at a concentration of 100 nM dexamethasone after treatment for 6 to 12 h and is greatly diminished by RU486. A similar pattern of expression is observed with tyrosine aminotransferase mRNA. Moreover, the effect of dexamethasone on PXR mRNA accumulation seems to be through direct action on the glucocorticoid receptor (GR) because the addition of cycloheximide has no effect, and dexamethasone does not affect the degradation of PXR mRNA. Furthermore, dexamethasone induces the accumulation of a RXR␣-immunoreactive protein and increases the nuclear level of RXR␣:PXR heterodimer as shown by gel shift assays with a CYP3A4 ER6 PXRE probe. This accumulation of latent PXR and RXR␣ in the nucleus of hepatocytes explains the synergistic effect observed with dexamethasone and PXR activators together on CYP3A4 induction. These results reveal the existence of functional cross talk between the GR and PXR, and may explain some controversial aspects of the role of the GR in CYP3A4 induction.

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The Fetal Specific GeneCYP3A7Is Inducible by Rifampicin in Adult Human Hepatocytes in Primary Culture

Cited by 52 publications

References 0 publications

Interindividual Variability and Tissue-Specificity in the Expression of Cytochrome P450 3A mRNA

Interindividual Variability and Tissue-Specificity in the Expression of Cytochrome P450 3A mRNA

Induction of Multidrug Resistance-1 and Cytochrome P450 mRNAs in Human Mononuclear Cells by Rifampin

Dexamethasone Induces Pregnane X Receptor and Retinoid X Receptor-α Expression in Human Hepatocytes: Synergistic Increase of CYP3A4 Induction by Pregnane X Receptor Activators

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