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Title: Increases in CYP3A Expression and Glucocorticoid-Inducibility in Liver of Rats Fed Soy Protein Isolate (SPI) Involves Post-Transcriptional Effects on mRNA Processing

Author
item RONIS, MARTIN - ACNC/UAMS
item CHEN, YING - ACNC/UAMS
item LIU, XIAOLI - ACNC/UAMS
item SHANKAR, KARTIK - ACNC/UAMS
item BADGER, THOMAS - ACNC/UAMS

Submitted to: Federation of American Societies for Experimental Biology Conference
Publication Type: Abstract Only
Publication Acceptance Date: 11/15/2006
Publication Date: 4/28/2007
Citation: Ronis, M.J., Chen, Y., Liu, X., Shankar, K., Badger, T.M. 2007. Increases in CYP3A expression and glucocorticoid-inducibility in liver of rats fed soy protein isolate (SPI) involves post-transcriptional effects on mRNA processing [abstract]. The FASEB Journal. 21(5):A372.

Interpretive Summary: Over 1 million American infants are fed soy formula every year. We have been studying the effects of soy formula on development and health on children in comparison to breast feeding and feeding milk-based formula. We have previously shown that feeding soy protein isolate (SPI), the sole protein in soy infant formulas, to rats in early life increased amounts of protein and activity of a family of liver enzymes known as the cytochrome P450 (CYP) 3As. These enzymes are involved in breaking down a large proportion of medications used in children, thus they are extremely important. We found that young rats fed soy protein, similar to that fed to American infants, had greatly elevated levels of these enzymes. If these increases observed in the current study in rats occur in children, it may result in altered clearance and efficacy of pediatric drugs in soy-formula fed infants compared to those fed dairy formula or breast milk. This is important to confirm, as it could result in a lower efficacy of these medications. Future work will focus on the consequences of these effects and on studies in children.

Technical Abstract: We analyzed a time course of dexamethasone (DEX)-induction at PND25 and PND60 in male and female rats fed soy protein isolate (SPI) or casein (CAS) based AIN93G diets throughout development to examine molecular mechanisms underlying increased CYP3A expression and inducibility after SPI-feeding. At PND25, SPI-feeding increased CYP3A1 and CYP3A2 mRNA expression (p < 0.05) only in male liver but increased CYP3A expression (p < 0.05) in both sexes at PND60. After 50 mg/kg DEX, CYP3A1 mRNA expression was induced >200-fold in SPI-fed males and females peaking 17 h post-injection but only 100- to 150-fold in CAS-fed animals (p < 0.05). A similar increase in DEX-inducibility was observed in CYP3A1 at PND60. CYP3A2 mRNA was also induced more in SPI-fed rats, but DEX-induction was only 2- to 4-fold. Measurement of steady-state HnRNA for CYP3A1 using RT-PCR with intron-specific primers showed no difference with diet and only 3- to 4-fold induction peaking at 8 h post-DEX. Quantitation of newly synthesized CYP3A1 RNA transcripts by nuclear run-on analysis using biotinylated nucleotides followed by avidin-bead precipitation and real-time RT-PCR demonstrated dramatic induction 8 h post-DEX, but no effects of diet on constitutive or induced levels of transcription. These data suggest that primary transcripts of CYP3A have a short half life relative to its mature mRNA and that while DEX increases transcription, increased mRNA expression and inducibility following SPI-feeding involves post-transcriptional effects on RNA processing.