Diets containing soy protein isolate increase hepatic CYP3A expression and inducibility in weanling male rats exposed during early development.
Hepatic CYP3A enzymes were studied in weanling male Sprague-Dawley rats exposed to diets from gestational d 4 in which the sole protein source was either casein (CAS) or soy protein isolate (SPI). At age 25 d, rats were gavaged with corn oil or one of the CYP3A inducers, dexamethasone (DEX) and clotrimazole (CLT), at a dose of 50 mg/kg. Little CYP3A1 (CYP3A23), CYP3A2, or CYP3A9 mRNA was observed in CAS-fed weanling rats but CYP3A18 mRNA was readily detectable in Northern blots. In contrast, consumption of SPI without inducer treatment resulted in the expression of CYP3A1 (CYP3A23), and CYP3A2 mRNAs, expression of CYP3A apoprotein in hepatic microsomes, and a 2-fold greater turnover of the CYP3A substrate midazolam (P < 0.05). DEX induced CYP3A1, CYP3A2, and CYP3A9 (P < 0.05), but not CYP3A18 mRNA expression in rats fed both diets. Hepatic CYP3A apoprotein expression and midazolam 4-hydroxylation in SPI-fed rats was greater than that of CAS-fed rats after DEX treatment (P < 0.05). CLT also induced CYP3A2 mRNA 2-fold in rats fed both diets but CYP3A apoprotein expression in microsomes from SPI-fed CLT rats was double that of CLT-treated rats fed CAS (P < 0.05). The elevation of CYP3A apoprotein due to SPI and the CYP3A apoprotein induction by DEX and CLT treatment yielded no significant diet x inducer interaction. Analysis of heterologous nuclear RNA expression by RT-PCR using intron-specific primers for CYP3A1 revealed a 14-fold increase in RNA transcription in CAS-fed rats after treatment with DEX (P < 0.05) but no increase in rats fed SPI compared with rats fed CAS even though CYP3A1 mRNA and CYP3A apoprotein were significantly elevated. These data demonstrate that exposure to SPI during early development can increase CYP3A expression via post-transcriptional mechanisms and suggest that early soy consumption has potential effects on the metabolism of a wide variety of CYP3A substrates.
Ronis
Martin J
MJ
Arkansas Children's Nutrition Center, Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. RonisMartinJ@uams.edu
Chen
Ying
Y
Jo
Chan-He
CH
Simpson
Pippa
P
Badger
Thomas M
TM
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001483:Base Sequence; D015152:Blotting, Northern; D003022:Clotrimazole / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D015342:DNA Probes; D018076:DNA, Complementary; D003907:Dexamethasone / Q000494:pharmacology; D004044:Dietary Proteins / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D030262:Soybean Proteins / Q000494:pharmacology*; D013739:Testosterone / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
D015342:DNA Probes; D018076:DNA, Complementary; D004044:Dietary Proteins; D012333:RNA, Messenger; D030262:Soybean Proteins; D013739:Testosterone; D003907:Dexamethasone; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D003022:Clotrimazole; D008874:Midazolam