Capsaicin induces CYP3A4 expression via pregnane X receptor and CCAAT/enhancer-binding protein β activation

• Published in: Molecular nutrition & food research 2012-05, Vol.56 (5), p.797-809
• Main Authors: Han, Eun Hee, Kim, Hyung Gyun, Choi, Jae Ho, Jang, Yin-Jin, Lee, Sang Seop, Kwon, Kwang-il, Kim, Eunyoung, Noh, Kyeumhan, Jeong, Tae Cheon, Hwang, Yong Pil, Chung, Young Chul, Kang, Wonku, Jeong, Hye Gwang
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; C/EBPβ; Capsaicin; Capsaicin - pharmacology; CCAAT-Enhancer-Binding Protein-beta - genetics; CCAAT-Enhancer-Binding Protein-beta - metabolism; CYP3A4; Cytochrome P-450 CYP3A - genetics; Cytochrome P-450 CYP3A - metabolism; Food industries; Food-Drug Interactions; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Hep G2 Cells; Humans; Inactivation, Metabolic; Liver - drug effects; Liver - metabolism; Male; Nifedipine - analogs & derivatives; Nifedipine - blood; Nifedipine - pharmacokinetics; Pregnane X Receptor; Promoter Regions, Genetic - drug effects; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; PXR; Rats; Rats, Sprague-Dawley; Receptors, Steroid - genetics; Receptors, Steroid - metabolism; Signal Transduction - drug effects; TRPV Cation Channels - metabolism; Up-Regulation
• ISSN: 1613-4125; 1613-4133
• DOI: 10.1002/mnfr.201100697

Scope 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. Methods and 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. Conclusion 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.