Induction of the Cytochrome P450 3A Subfamily in Rat Liver Correlates with the Binding of Inducers to a Microsomal Protein

Wright, Matthew C.; Paine, Alan J.

doi:10.1006/bbrc.1994.1797

Cited by 27 publications

(20 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The dexamethasone inhibitory effect increased in a concentration-dependent fashion with 50% of maximal inhibition occurring at 1 nmol/L ( Fig. 4), which is in agreement with the reported K d value for the rat GR 35 and implied that the inhibitory effect is through activation of this type of receptor, without any effect on JNK protein levels.…”

Section: Effect Of Dexamethasone On Jnk Activity Induced By Tnf-␣supporting

confidence: 89%

Glucocorticoid receptor down-Regulates c-jun amino terminal kinases induced by tumor necrosis factor ? in fetal rat hepatocyte primary cultures

et al. 1999

View full text Add to dashboard Cite

The effect of dexamethasone on Jun N-terminal kinase (JNK) activity was assayed by using fetal hepatocytes in primary culture. The addition of tumor necrosis factor ␣ (TNF-␣) caused an increase in JNK in a dose-and timedependent manner. We show that activation of JNK by this extracellular signal is inhibited by dexamethasone in a dose-dependent fashion. This inhibitory effect was observed in cells treated for 10 minutes with dexamethasone in the presence of protein phosphatase inhibitors such as orthovanadate or okadaic acid, or in cells previously treated with actinomycin D. Glucocorticoid receptor (GR) can be precipitated with the fusion protein, GST-c-Jun (1-79), bound to agarose beads. However, the inhibitory effect of glucocorticoids on JNK activity was also observed using ATF-2 as substrate. In addition, dexamethasone inhibits JNK phosphorylation induced by TNF-␣. Finally, we show that GR can also be phosphorylated in tyrosine residues in response to TNF-␣ and epidermal growth factor (EGF) upon ligand-binding. Our results suggest that the antiinflammatory effect of glucocorticoids on the inflammatory pathways induced by TNF-␣ can be explained, at least in part, by modulating JNK activity through a direct proteinprotein interaction; the JNK phosphorylation and tyrosinephosphorylation state of GR may be regulatory steps also involved in that effect. (HEPATOLOGY 1999;29:849-857.)

show abstract

Section: Effect Of Dexamethasone On Jnk Activity Induced By Tnf-␣supporting

confidence: 89%

Glucocorticoid receptor down-Regulates c-jun amino terminal kinases induced by tumor necrosis factor ? in fetal rat hepatocyte primary cultures

et al. 1999

View full text Add to dashboard Cite

show abstract

“…MDRl is known to be downregulated by the tumor suppressor p53 [77], and CYP3A4 has been demonstrated to possess a p53 binding motif [78]. Moreover, inhibition of a repressor has been proposed as a mechanism of dexamethasone-mediated CYP3A induction [79]. Hence, the effects of DRA, p53, and other possible suppressor gene products on the concomitant expression of CYP3A and P-gp may provide another area of overlapping regulation for these genes.…”

Section: Possible Coordinate Regulation Of Cyp3a and P-gp Gene Expresmentioning

confidence: 97%

“…CYP3A induction has been shown t o proceed independently of the native glucocorticoid receptor [ 100,101], correlating instead with dexamethasone binding to a microsomal protein [79], and P-gp induction does not appear to require direct dexamethasone-receptor-DNA interaction [55,102]. It has been suggested that the inductive effect of dexamethasone on both CYP3A [91] and P-gp induction [I021 is exerted at the level of early cell differentiation [91,1021, and, although no mechanisms have been proposed, this also provides another interesting area of possible overlap between P-gp and CYP3A regulatory processes.…”

Section: Effects Of Hormones On Cyp3a and P-gp Expressionmentioning

confidence: 99%

Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P‐glycoprotein: Implications for drug delivery and activity in cancer chemotherapy

Wacher

Benet

1995

Molecular Carcinogenesis

790

455

View full text Add to dashboard Cite

“…Group 3 was treated with dexamethasone (DEX) (100 mg/kg, i.p. × 3 days in corn oil, CYP3A1/ 2) (Wright and Paine, 1994). Group 4 served as a control; these rats were treated with an equivalent volume of corn oil.…”

Section: Induction Of Pd-ia Metabolismmentioning

confidence: 99%

Metabolism of dl-praeruptorin a in rat liver microsomes using HPLC-electrospray ionization tandem mass spectrometry

et al. 2011

View full text Add to dashboard Cite

dl-Praeruptorin A (Pd-Ia) is the major active constituent of the traditional Chinese medicine Peucedanum praeruptorum Dunn. Recently it has been identified as a novel agent in the treatment and prevention of cardiovascular diseases. Accordingly, we investigated the metabolism of Pd-Ia in rat liver microsomes. The involvement of cytochrome P450 (CYP) and CYP isoforms were identified using a CYP-specific inhibitor (SKF-525A), CYP-selective inhibitors (α-naphthoflavone, metyrapone, fluvastatin, quinidine, disulfiram, ketoconazole and ticlopidine) and CYP-selective inducers (phenobarbital, dexamethasone and β-naphthoflavone). Residual concentrations of the substrate and metabolites were determined by HPLC, and further identified by their mass spectra and chromatographic behavior. These experiments showed that CYP450 is involved in Pd-Ia metabolism, and that the major CYP isoform responsible is CYP3A1/2, which acts in a concentration-dependent manner. Four Pd-Ia metabolites (M1, M2, M3, and M4) were detected after incubation with rat liver microsomes. Hydroxylation was the primary metabolic pathway of Pd-Ia, and possible chemical structures of the metabolites were identified. Further research is now needed to link the metabolism of Pd-Ia to its drug-drug interactions.

show abstract

Induction of the Cytochrome P450 3A Subfamily in Rat Liver Correlates with the Binding of Inducers to a Microsomal Protein

Cited by 27 publications

References 0 publications

Glucocorticoid receptor down-Regulates c-jun amino terminal kinases induced by tumor necrosis factor ? in fetal rat hepatocyte primary cultures

Glucocorticoid receptor down-Regulates c-jun amino terminal kinases induced by tumor necrosis factor ? in fetal rat hepatocyte primary cultures

Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P‐glycoprotein: Implications for drug delivery and activity in cancer chemotherapy

Metabolism of dl-praeruptorin a in rat liver microsomes using HPLC-electrospray ionization tandem mass spectrometry

Contact Info

Product

Resources

About