Enhanced Expression and Glucocorticoid-Inducibility of Hepatic Cytochrome P450 3A Involve Recruitment of the Pregnane-X-Receptor to Promoter Elements in Rats Fed Soy Protein Isolate

Abstract

Previous studies and Expt. 1 of the current study demonstrate that diets made with soy protein isolate (SPI) enhance the glucocorticoid-inducibility of hepatic cytochrome P450 (CYP)3A-dependent monooxygenase activities (P < 0.05) compared with diets made with casein (CAS). To determine the underlying molecular mechanism, in a second experiment, we analyzed the time course of dexamethasone (DEX)-induction of hepatic CYP3A mRNA expression on postnatal d (PND) 25 and PND60 in male and female rats fed SPI- or CAS-based diets. After 50 mg/kg DEX, CYP3A1 mRNA expression increased >200-fold in SPI-fed males and females at PND25 compared with a 100-fold increase in CAS-fed rats (P < 0.05). The DEX-induced increase in CYP3A1 mRNA in SPI-fed rats on PND60 was also greater than that in CAS-fed rats. The induction by DEX of CYP3A2 mRNA was 1- to 3-fold greater in rats fed SPI compared with those fed CAS on PND25 (P < 0.05). Quantitation of newly synthesized CYP3A1 RNA transcripts by nuclear run-on analysis demonstrated a greater rate of basal transcription in SPI-fed compared with CAS-fed rats on PND60 accompanied by greater binding of the pregnane X receptor (PXR) to a response element on the CYP3A1 promoter in SPI-fed compared with CAS-fed rats (P < 0.05). These data suggest that increased hepatic CYP3A expression and inducibility following SPI feeding involves recruitment of PXR to its response element and suggests that soy consumption has potential effects on metabolism and transport of a wide variety of drugs and on bile acid homeostasis via proteins regulated by this transcription factor.