Capsaicin induces CYP3A4 expression via pregnane X receptor and CCAAT/enhancer-binding protein β activation.
METHODS
Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is the principal pungent ingredient in hot red and chili peppers. Many studies have focused on the anticarcinogenic or chemopreventive activities of capsaicin. However, the influence of capsaicin on CYP3A4, its involvement in drug metabolism, and the underlying mechanisms remain unclear.


RESULTS
Here, we examined the effect of capsaicin on CYP3A4 expression and the metabolism of CYP3A1 substrate, nifedipine in male Sprague-Dawley rats. Capsaicin induced the enzymatic activity and expression of CYP3A4 in HepG2 cells. Treatment with a human pregnane X receptor (hPXR) inhibitor reduced the inductive effects of capsaicin on CYP3A4 expression. Capsaicin also induced the activation of CCAAT/enhancer-binding protein β (C/EBPβ). Moreover, capsaicin increased the activation of the transient receptor potential vanilloid type-1 receptor downstream signaling components Ca²⁺/calmodulin-dependent protein kinase and Akt. Capsaicin elevated the level of CYP3A1 in rat liver and significantly increased the biotransformation of nifedipine to dehydronifedipine.


CONCLUSIONS
From these data, we conclude that capsaicin induces CYP3A4 expression in vitro and in vivo. This induction was achieved by the activation of hPXR and C/EBPβ. Our results suggest that capsaicin might induce CYP3A4 expression; thus, exposure to capsaicin may increase the metabolism of CYP3A4 substrate and potentially cause food-drug interactions.
Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
Eun Hee
EH
Han
Hyung Gyun
HG
Kim
Jae Ho
JH
Choi
Yin-Jin
YJ
Jang
Sang Seop
SS
Lee
Kwang-Il
KI
Kwon
Eunyoung
E
Kim
Kyeumhan
K
Noh
Tae Cheon
TC
Jeong
Yong Pil
YP
Hwang
Young Chul
YC
Chung
Wonku
W
Kang
Hye Gwang
HG
Jeong
D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics* / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D018565:Food-Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009543:Nifedipine / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D050916:TRPV Cation Channels / Q000378:metabolism; D015854:Up-Regulation
D022782:CCAAT-Enhancer-Binding Protein-beta; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C117802:dehydronifedipine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D051057:Proto-Oncogene Proteins c-akt; D009543:Nifedipine; D002211:Capsaicin