Down-Regulation of Cytochrome P450 2C Family Members and Positive Acute-Phase Response Gene Expression by Peroxisome Proliferator Chemicals

Corton, J C; Fan, Liqing; Brown, Sherri S.; Anderson, Steven P.; Bocos, Carlos; Cattley, Russell C.; Mode, Agneta; Gustafsson, Jan‐Åke

doi:10.1124/mol.54.3.463

Cited by 97 publications

(76 citation statements)

References 39 publications

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“…Ciprofibrate and the inhibitors were without effect on CYP2C expression, either in the absence or presence of ciprofibrate. The lack of ciprofibrate effect on CYP2C11 level is in agreement with published data showing that downregulation of CYP2C occurs only after 48 h of exposure of hepatocytes to the strong PP WY-14,643 (43). A short (12 h) exposure to ciprofibrate was used in our experiments, which also explains the low, although significant, effect of ciprofibrate on CYP4A expression.…”

Section: Resultssupporting

confidence: 80%

P450 CYP2C epoxygenase and CYP4A ω-hydroxylase mediate ciprofibrate-induced PPARα-dependent peroxisomal proliferation

Gatica

Aguilera

Contador

et al. 2007

Journal of Lipid Research

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Peroxisomal proliferators, such as ciprofibrate, are used extensively as effective hypolipidemic drugs. The effects of these compounds on lipid metabolism require ligand binding activation of the peroxisome proliferatoractivated receptor (PPAR) a subtype of nuclear receptors and involve transcriptional activation of the metabolic pathways involved in lipid oxidative metabolism, transport, and disposition. v-Hydroxylated-eicosatrienoic acids (HEETs), products of the sequential metabolism of arachidonic acid (AA) by the cytochrome P450 CYP2C epoxygenase and CYP4A v-hydroxylase gene subfamilies, have been identified as potent and high-affinity ligands of PPARa in vitro and as PPARa activators in transient transfection assays. Using isolated rat hepatocytes in culture, we demonstrate that specific inhibition of either the CYP2C epoxygenase or the CYP4A v-hydroxylase abrogates ciprofibrate-induced peroxisomal proliferation, whereas inhibition of other eicosanoid-synthesizing pathways had no effect. Conversely, overexpression of the rat liver CYP2C11 epoxygenase leads to spontaneous peroxisomal proliferation, an effect that is reversed by a CYP inhibitor. Based on these results, we propose that HEETs may serve as endogenous PPARa ligands and that the P450 AA monooxygenases participate in ciprofibrate-induced peroxisomal proliferation and the activation of PPARa downstream targets.-Gatica, A

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Section: Resultssupporting

confidence: 80%

P450 CYP2C epoxygenase and CYP4A ω-hydroxylase mediate ciprofibrate-induced PPARα-dependent peroxisomal proliferation

Gatica

Aguilera

Contador

et al. 2007

Journal of Lipid Research

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“…The decreased PPAR␣ expression strongly correlated with the reduced expression levels of Cyp2d22 and Cyp2e1 ( Table 2), suggesting that PPAR␣ potentially participates in regulation of P450 expression during mouse pregnancy. In fact, it has been shown that a peroxisome proliferator activator (such as WY-14,643) down-regulates CYP2C11 and CYP2C12 while up-regulating CYP4A in rats (Corton et al, 1998;Graham and Lake, 2008) and mice (Savas et al, 2009). However, it is uncertain whether these results can be extrapolated to humans.…”

Section: Discussionmentioning

confidence: 90%

Altered Cytochrome P450 Expression in Mice during Pregnancy

Koh¹,

Xie²,

Yu³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Human pregnancy is known to influence hepatic drug metabolism in a cytochrome (P450)-specific manner. However, the underlying mechanisms remain unknown, in part due to a lack of experimental models to study altered drug metabolism during pregnancy. In this study, we examined how pregnancy influences expression of major P450 isoforms in mice. Liver tissues were isolated from female FVB/N-mice at different gestational time points: prepregnancy, 7, 14, and 21 days of pregnancy, and 7 days postpartum. mRNA expression levels of major P450 isoforms (Cyp1a2, Cyp2a5, Cyp2b10, Cyp2c37, Cyp2d22, Cyp2e1, Cyp3a11, and Cyp3a41) in the liver tissues were determined by quantitative real-time polymerase chain reaction. Whereas Cyp2a5 expression was unchanged, Cyp3a41 expression was significantly increased during pregnancy. In contrast, expression of Cyp1a2, Cyp2c37, Cyp2d22, Cyp2e1, and Cyp3a11 was decreased. Expression of Cyp2d22 and Cyp2e1 isoforms correlated with that of peroxisome proliferatoractivated receptor (PPAR)␣ in the mouse livers, suggesting potential involvement of PPAR␣ in down-regulation of the P450 expression during pregnancy. Effects of pregnancy on expression of other P450 mouse isoforms as well as on in vivo drug disposition remain to be characterized. These results provide a guide for future studies on P450 regulation during pregnancy.

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“…In the present study, down-regulation of genes classified to the immune response and coagulation was also in vivo-specific. PPARα is known to function as an inhibitory factor for inflammation, and PPARα agonists were reported to inhibit the expression of mRNA of fibrinogen, an acute phase protein (Kockx et al, 1999;Corton et al, 1998), and induction of fibrinogen gene by IL-6 (Gervois et al, 2001). Moreover, it was also reported that WY-14643 inhibits induction of IL-6 and cyclooxygenase-2 by IL-1 in human aortic smooth muscle cells through inhibition of the translocation of NF-κB from the cytosol to the nucleus.…”

Section: Discussionmentioning

confidence: 99%

Profiling of Gene Expression in Rat Liver and Rat Primary Cultured Hepatocytes Treated With Peroxisome Proliferators

et al. 2006

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-The Toxicogenomics project has been constructing a large-scale database of about 150 compounds exposed to rat (single dose, 3, 6, 9, 24 hrs and repeated dose for 3, 7, 14 28 days with 3 dose levels) and rat hepatocytes (2, 8, 24 hr with 3 concentrations) and data of transcriptome in liver using GeneChip, and the related toxicological measures are being accumulated. In the present study, the data of three ligands of peroxisome proliferator activated receptor α (PPARα), i.e., clofibrate, WY-14643 and gemfibrozil in our database were analyzed. Many of the β-oxidation-related genes were commonly induced in vivo and in vitro, whereas expression changes in genes related to cell proliferation, apoptosis, were detected in vivo (single and repeated dose) but not in vitro. Changes in those related to the immune response, coagulation and the stress response were also detectable exclusively in vivo. Using the genes mobilized in two or three PPARα agonists, hierarchical clustering was performed on 32 compounds stored in our database. In the profiling of an in vivo single dose, benzbromarone and aspirin were located in the same cluster of the three PPARα agonists. The clustering of in vitro data revealed that benzbromarone, three NSAIDs (aspirin, indomethacin and diclofenac sodium) and valproic acid belonged to the same cluster of PPARα agonists, supporting the reports that benzbromarone,valproic acid and some NSAIDs were reported to be PPARα agonists. Using the genes commonly up-regulated both in vivo and in vitro, principal component analysis was performed in 32 compounds, and principal component 1 was found to be the convenient parameter to extract PPARα agonist-like compounds from the database.

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Down-Regulation of Cytochrome P450 2C Family Members and Positive Acute-Phase Response Gene Expression by Peroxisome Proliferator Chemicals

Cited by 97 publications

References 39 publications

P450 CYP2C epoxygenase and CYP4A ω-hydroxylase mediate ciprofibrate-induced PPARα-dependent peroxisomal proliferation

P450 CYP2C epoxygenase and CYP4A ω-hydroxylase mediate ciprofibrate-induced PPARα-dependent peroxisomal proliferation

Altered Cytochrome P450 Expression in Mice during Pregnancy

Profiling of Gene Expression in Rat Liver and Rat Primary Cultured Hepatocytes Treated With Peroxisome Proliferators

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