Pregnane X Receptor-Dependent Induction of the CYP3A4 Gene by o,p′-1,1,1,-Trichloro-2,2-Bis (p-Chlorophenyl)ethane

Medina-Díaz, Irma Martha; Arteaga-Illán, Georgina; León, Mario Bermúdez de; Cisneros, Bulmaro; Sierra-Santoyo, Adolfo; Vega, Libia; Gonzalez, Frank J.; Elizondo, Guillermo

doi:10.1124/dmd.106.011759

Cited by 26 publications

(11 citation statements)

References 40 publications

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“…The flexibility of the LBD likely enables SXR to recognize a wide range of xenobiotics, including mitotane. It is noteworthy that DDT, from which mitotane is derived, has been reported to be a potent activator of human SXR as well (Medina-Diaz & Elizondo 2005, Medina-Diaz et al 2007). Thus, mitotanebound SXR recruits p160 coactivators to induce CYP3A4 gene expression.…”

Section: Discussionmentioning

confidence: 99%

Mitotane induces CYP3A4 expression via activation of the steroid and xenobiotic receptor

Takeshita¹,

Igarashi-Migitaka²,

Koibuchi³

et al. 2012

Journal of Endocrinology

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Adrenocortical carcinoma (ACC) is a rare disease with an extremely poor prognosis. Mitotane alone or in combination with other cytotoxic drugs is a common therapeutic option for ACC. In addition to its adrenolytic function, mitotane has been known for decades to increase the metabolic clearance of glucocorticoids. It was recently shown that the tyrosine kinase inhibitor sunitinib is also rapidly metabolized in patients treated with mitotane, indicating that mitotane engages in clinically relevant drug interactions. Although the precise mechanism of these interactions is not well understood, cytochrome P450 mono-oxygenase 3A4 (CYP3A4) is a key enzyme to inactivate both glucocorticoids and sunitinib. The nuclear receptor steroid and xenobiotic receptor (SXR (NR1I2)) is one of the key transcriptional regulators of CYP3A4 gene expression in the liver and intestine. A variety of xenobiotics bind to SXR and stimulate transcription of xenobiotic-response elements (XREs) located in the CYP3A4 gene promoter. In this study, we evaluated the effects of mitotane on SXR-mediated transcription in vitro by luciferase reporter analysis, SXR-steroid receptor coactivator 1 (SRC1) interactions, quantitative real-time PCR analysis of CYP3A4 expression, SXR knockdown, and CYP3A4 enzyme activity assays using human hepatocyte-derived cells. We found that mitotane activated SXR-mediated transcription of the XREs. Mitotane recruited SRC1 to the ligand-binding domain of SXR. Mitotane increased CYP3A4 mRNA levels, which was attenuated by SXR knockdown. Finally, we showed that mitotane increased CYP3A4 enzyme activity. We conclude that mitotane can induce CYP3A4 gene expression and suggest that mitotane is used cautiously due to its drug-drug interactions.

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Section: Discussionmentioning

confidence: 99%

Mitotane induces CYP3A4 expression via activation of the steroid and xenobiotic receptor

Takeshita¹,

Igarashi-Migitaka²,

Koibuchi³

et al. 2012

Journal of Endocrinology

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“…op'-DDT had been reported as a ligand of rCAR, mCAR, and SXR Medina et al, 2007;Wyde et al, 2003). However, it remains to be addressed whether pp'-DDT is also an agonist of hCAR.…”

Section: Identification Of Dtt As a Ligand Of Hcar By A Novel Car Ligmentioning

confidence: 99%

A consecutive three alanine residue insertion mutant of human CAR: a novel CAR ligand screening system in HepG2 cells

Kanno

Inouye

2010

J. Toxicol. Sci.

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-The expression of the CAR gene is lost in most cultured cell lines, and exogenously expressed CAR accumulates spontaneously in the nuclear compartment, where CAR is constitutively active. Therefore, the assessment of CAR-dependent transcriptional activation has to be evaluated using either animal models or primary cultured hepatocytes. Furthermore, due to the species-specific response of CAR to individual compounds, the results obtained with animal models are not directly applicable to human cases. We established a novel screening system for hCAR ligands (including agonists and inverse agonists) by expressing GAL4/DBD-fused hCAR/LBD, in which three consecutive alanine residues were inserted between helix 11 and helix 12 of LBD, and a commercially obtained plasmid consisting of the firefly luciferase gene downstream of the GAL4 responsive element in a cultured cell line. Androstenol (Andro) and clotrimazole (CLT), which are both inverse agonists of hCAR, were classified as an antagonist and weak agonist, respectively, in our novel assay system. Among DDT and its metabolites DDE and DDD, only DDT worked as an agonist of the hCAR mutant, although all of them were enrolled as agonists of SXR. Using this system, the screening for hCAR ligands can be conducted without sacrificing animals.

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“…On the other hand, upregulation of Cyp7b1 and Cyp17a1 (Table 9), and downregulation of Cyp7a1, expression by o,p'-DDT was mediated by the estrogen receptor [412]. o,p'-DDT induced human PXR-mediated CYP3A4 and mouse Cyp3a11 mRNA expression in intestine of CYP3A4-transgenic mice [381].…”

Section: Pregnane X Receptor (Pxr)mentioning

confidence: 97%

Expression, Function and Regulation of Mouse Cytochrome P450 Enzymes: Comparison With Human Cytochrome P450 Enzymes

Hrycay

Bandiera

2009

CDM

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The present review focuses on the expression, function and regulation of mouse cytochrome P450 (Cyp) enzymes. Information compiled for mouse Cyp enzymes is compared with data collected for human CYP enzymes. To date, approximately 40 pairs of orthologous mouse-human CYP genes have been identified that encode enzymes performing similar metabolic functions. Recent knowledge concerning the tissue expression of mouse Cyp enzymes from families 1 to 51 is summarized. The catalytic activities of microsomal, mitochondrial and recombinant mouse Cyp enzymes are discussed and their involvement in the metabolism of exogenous and endogenous compounds is highlighted. The role of nuclear receptors, such as the aryl hydrocarbon receptor, constitutive androstane receptor and pregnane X receptor, in regulating the expression of mouse Cyp enzymes is examined. Targeted disruption of selected Cyp genes has generated numerous Cyp null mouse lines used to decipher the role of Cyp enzymes in metabolic, toxicological and biological processes. In conclusion, the laboratory mouse is an indispensable model for exploring human CYP-mediated activities.

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Pregnane X Receptor-Dependent Induction of the CYP3A4 Gene by o,p′-1,1,1,-Trichloro-2,2-Bis (p-Chlorophenyl)ethane

Cited by 26 publications

References 40 publications

Mitotane induces CYP3A4 expression via activation of the steroid and xenobiotic receptor

Mitotane induces CYP3A4 expression via activation of the steroid and xenobiotic receptor

A consecutive three alanine residue insertion mutant of human CAR: a novel CAR ligand screening system in HepG2 cells

Expression, Function and Regulation of Mouse Cytochrome P450 Enzymes: Comparison With Human Cytochrome P450 Enzymes

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