Pregnane X receptor-dependent induction of the CYP3A4 gene by o,p′-1,1,1,-trichloro-2,2-bis (p-chlorophenyl)ethane

Irma M. Medina-Díaz, Georgina Arteaga-Illán, Mario Bermudez De León, Bulmaro Cisneros, Adolfo Sierra-Santoyo, Libia Vega, Frank J. Gonzalez, Guillermo Elizondo

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

CYP3A4, the predominant cytochrome P450 (P450) expressed in human liver and intestine, contributes to the metabolism of approximately half the drugs in clinical use today. CYP3A4 catalyzes the 6β-hydroxylation of a number of steroid hormones and is involved in the bioactivation of environmental procarcinogens. The expression of CYP3A4 is affected by several stimuli, including environmental factors such as insecticides and pesticides. The o,p′-1,1,1,-trichloro-2,2-bis (p-chlorophenyl)ethane (DDT) isomer of DDT comprises approximately 20% of technical grade DDT, which is an organochloride pesticide. We have recently shown that o,p′-DDT exposure increases CYP3A4 mRNA levels in HepG2 cells. To determine the mechanism by which o,p′-DDT induces CYP3A4 expression, transactivation and electrophoretic mobility shift assays were carried out, revealing that o,p′-DDT activates the CYP3A4 gene promoter through the pregnane X receptor (PXR). CYP3A4 gene promoter activation resulted in both an increase in CYP3A4 mRNA levels and an increase in the total CYP3A4 activity in HepG2 cells. We also observed induction of CYP3A4 and mouse Cyp3a11 mRNA in the intestine of CYP3A4-transgenic mice after exposure to 1 mg/kg o,p′-DDT. At higher doses, a decrease of CYP3A4 inducibility was observed together with an increase in levels of interleukin 6 mRNA, a proinflammatory cytokine that strongly represses CYP3A4 transcription. The present study indicates that regulation of other genes under PXR control may be altered by o,p′-DDT exposure.
Original languageEnglish
Pages (from-to)95-102
Number of pages8
JournalDrug Metabolism and Disposition
DOIs
Publication statusPublished - 8 Jan 2007
Externally publishedYes

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Cytochrome P-450 CYP3A
DDT
Genes
Messenger RNA
Hep G2 Cells
Pesticides
pregnane X receptor
Transcriptional Activation
Intestines
Electrophoretic Mobility Shift Assay
Hydroxylation
Insecticides
Cytochrome P-450 Enzyme System
Transgenic Mice
Interleukin-6

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

Cite this

Medina-Díaz, Irma M. ; Arteaga-Illán, Georgina ; De León, Mario Bermudez ; Cisneros, Bulmaro ; Sierra-Santoyo, Adolfo ; Vega, Libia ; Gonzalez, Frank J. ; Elizondo, Guillermo. / Pregnane X receptor-dependent induction of the CYP3A4 gene by o,p′-1,1,1,-trichloro-2,2-bis (p-chlorophenyl)ethane. In: Drug Metabolism and Disposition. 2007 ; pp. 95-102.
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abstract = "CYP3A4, the predominant cytochrome P450 (P450) expressed in human liver and intestine, contributes to the metabolism of approximately half the drugs in clinical use today. CYP3A4 catalyzes the 6β-hydroxylation of a number of steroid hormones and is involved in the bioactivation of environmental procarcinogens. The expression of CYP3A4 is affected by several stimuli, including environmental factors such as insecticides and pesticides. The o,p′-1,1,1,-trichloro-2,2-bis (p-chlorophenyl)ethane (DDT) isomer of DDT comprises approximately 20{\%} of technical grade DDT, which is an organochloride pesticide. We have recently shown that o,p′-DDT exposure increases CYP3A4 mRNA levels in HepG2 cells. To determine the mechanism by which o,p′-DDT induces CYP3A4 expression, transactivation and electrophoretic mobility shift assays were carried out, revealing that o,p′-DDT activates the CYP3A4 gene promoter through the pregnane X receptor (PXR). CYP3A4 gene promoter activation resulted in both an increase in CYP3A4 mRNA levels and an increase in the total CYP3A4 activity in HepG2 cells. We also observed induction of CYP3A4 and mouse Cyp3a11 mRNA in the intestine of CYP3A4-transgenic mice after exposure to 1 mg/kg o,p′-DDT. At higher doses, a decrease of CYP3A4 inducibility was observed together with an increase in levels of interleukin 6 mRNA, a proinflammatory cytokine that strongly represses CYP3A4 transcription. The present study indicates that regulation of other genes under PXR control may be altered by o,p′-DDT exposure.",
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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. / Medina-Díaz, Irma M.; Arteaga-Illán, Georgina; De León, Mario Bermudez; Cisneros, Bulmaro; Sierra-Santoyo, Adolfo; Vega, Libia; Gonzalez, Frank J.; Elizondo, Guillermo.

In: Drug Metabolism and Disposition, 08.01.2007, p. 95-102.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pregnane X receptor-dependent induction of the CYP3A4 gene by o,p′-1,1,1,-trichloro-2,2-bis (p-chlorophenyl)ethane

AU - Medina-Díaz, Irma M.

AU - Arteaga-Illán, Georgina

AU - De León, Mario Bermudez

AU - Cisneros, Bulmaro

AU - Sierra-Santoyo, Adolfo

AU - Vega, Libia

AU - Gonzalez, Frank J.

AU - Elizondo, Guillermo

PY - 2007/1/8

Y1 - 2007/1/8

N2 - CYP3A4, the predominant cytochrome P450 (P450) expressed in human liver and intestine, contributes to the metabolism of approximately half the drugs in clinical use today. CYP3A4 catalyzes the 6β-hydroxylation of a number of steroid hormones and is involved in the bioactivation of environmental procarcinogens. The expression of CYP3A4 is affected by several stimuli, including environmental factors such as insecticides and pesticides. The o,p′-1,1,1,-trichloro-2,2-bis (p-chlorophenyl)ethane (DDT) isomer of DDT comprises approximately 20% of technical grade DDT, which is an organochloride pesticide. We have recently shown that o,p′-DDT exposure increases CYP3A4 mRNA levels in HepG2 cells. To determine the mechanism by which o,p′-DDT induces CYP3A4 expression, transactivation and electrophoretic mobility shift assays were carried out, revealing that o,p′-DDT activates the CYP3A4 gene promoter through the pregnane X receptor (PXR). CYP3A4 gene promoter activation resulted in both an increase in CYP3A4 mRNA levels and an increase in the total CYP3A4 activity in HepG2 cells. We also observed induction of CYP3A4 and mouse Cyp3a11 mRNA in the intestine of CYP3A4-transgenic mice after exposure to 1 mg/kg o,p′-DDT. At higher doses, a decrease of CYP3A4 inducibility was observed together with an increase in levels of interleukin 6 mRNA, a proinflammatory cytokine that strongly represses CYP3A4 transcription. The present study indicates that regulation of other genes under PXR control may be altered by o,p′-DDT exposure.

AB - CYP3A4, the predominant cytochrome P450 (P450) expressed in human liver and intestine, contributes to the metabolism of approximately half the drugs in clinical use today. CYP3A4 catalyzes the 6β-hydroxylation of a number of steroid hormones and is involved in the bioactivation of environmental procarcinogens. The expression of CYP3A4 is affected by several stimuli, including environmental factors such as insecticides and pesticides. The o,p′-1,1,1,-trichloro-2,2-bis (p-chlorophenyl)ethane (DDT) isomer of DDT comprises approximately 20% of technical grade DDT, which is an organochloride pesticide. We have recently shown that o,p′-DDT exposure increases CYP3A4 mRNA levels in HepG2 cells. To determine the mechanism by which o,p′-DDT induces CYP3A4 expression, transactivation and electrophoretic mobility shift assays were carried out, revealing that o,p′-DDT activates the CYP3A4 gene promoter through the pregnane X receptor (PXR). CYP3A4 gene promoter activation resulted in both an increase in CYP3A4 mRNA levels and an increase in the total CYP3A4 activity in HepG2 cells. We also observed induction of CYP3A4 and mouse Cyp3a11 mRNA in the intestine of CYP3A4-transgenic mice after exposure to 1 mg/kg o,p′-DDT. At higher doses, a decrease of CYP3A4 inducibility was observed together with an increase in levels of interleukin 6 mRNA, a proinflammatory cytokine that strongly represses CYP3A4 transcription. The present study indicates that regulation of other genes under PXR control may be altered by o,p′-DDT exposure.

U2 - 10.1124/dmd.106.011759

DO - 10.1124/dmd.106.011759

M3 - Article

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JO - Drug Metabolism and Disposition

JF - Drug Metabolism and Disposition

SN - 0090-9556

ER -