Received for publication June 30, 2006.
Revised October 5, 2006.
Accepted for publication October 6, 2006.

Pregnane X Receptor-dependent induction of the CYP3A4 gene by o,p-DDT

Abstract

Cytochrome P-450 3A4 (CYP3A4), the predominant cytochrome P450 (CYP) expressed in human liver and intestine, contributes to the metabolism of approximately half the drugs in clinical use today. CYP3A4 catalyzes the 6beta-hydroxylation of a number of steroid hormones, and is involved in the bioactivation of environmental pro-carcinogens. The expression of CYP3A4 is affected by several stimuli, including environmental factors such as insecticides and pesticides. The o,p’-DDT isomer of DDT [1,1,1,-trichloro-2,2-bis (p-chlorophenyl) ethane] comprises approximately 20% of technical grade DDT, which is an organochloride pesticide. We have recently demonstrated 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 reveling 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 following exposure to 1 mg/kg of 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.

Key words: CYP expression, CYP gene regulation, CYP3A, PXR, toxicology