|Ronis, Martin -|
|Chen, Ying -|
|Liu, Xioli -|
|Blackburn, Michael -|
|Shankar, Kartik -|
|Landes, Reid -|
|Fang, Nianba -|
Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: October 11, 2010
Publication Date: January 10, 2011
Citation: Ronis, M.J., Chen, Y., Liu, X., Blackburn, M., Shankar, K., Landes, R.D., Fang, N., Badger, T.M. 2011. Enhanced expression and glucocorticoid-inducibility of hepatic Ccytochrome P450 3A involve recruitment of the pregnane-x-receptor to promoter elements in rats fed soy protein isolate. Journal of Nutrition. 141(1):10-16. Interpretive Summary: We previously published data showing that feeding diets made with soy protein isolate (SPI), the sole protein found in soy infant formula, and a common component of processed foods, increases the breakdown and clearance of many drugs because of increased levels of a liver enzyme family: the cytochrome P450 (CYP) 3As. However, the molecular mechanisms underlying this effect remain unclear. In this report, we determined that transcription of CYP3A genes was increased after soy feeding and that this was associated with increased binding of a liver transcription factor PXR to the promoter region of CYP3A genes. PXR regulates a whole collection of liver genes, which control steroid and bile acid breakdown and transport in addition to regulation of CYP3As. These data suggest that soy consumption has potential effects on metabolism and transport of a wide variety of drugs, steroids, and bile acids via proteins regulated by this transcription factor.
Technical 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.