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A dual function of the furanocoumarin chalepensin in inhibiting Cyp2a and inducing Cyp2b in mice: the protein stabilization and receptor-mediated activation |
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| Authors: | Wei-Sheng Lo Yun-Ping Lim Chien-Chih Chen Chih-Chien Hsu Pavel Sou?ek Chul-Ho Yun Wen Xie Yune-Fang Ueng |
| Institution: | 1. National Research Institute of Chinese Medicine, No. 155-1, Li-Nong Street, Sec. 2, Taipei, 112, Taiwan, ROC 2. Department of Pharmacy, College of Pharmacy, China Medical University, 91 Hsueh-Shih Rd., Taichung, 404, Taiwan, ROC 3. Department of Emergency, Toxicology Center, China Medical University Hospital, Taichung, 404, Taiwan, ROC 4. Department of Biotechnology, Hungkuang University, No. 34, Chung-Chie Rd., Shalu, Taichung County, 433, Taiwan, ROC 5. Institute of Oral Biology, School of Dentistry, National Yang-Ming University, No. 155, Li-Nong Street, Sec. 2, Taipei, 112, Taiwan, ROC 6. Department of Toxicogenomics, National Institute of Public Health, ?robárova 48, 10042, Praha 10, Czech Republic 7. School of Biological Sciences and Technology, Chonnam National University, Gwangju, 500-757, Republic of Korea 8. Center for Pharmacogenetics, University of Pittsburgh, 633 Salk Hall, 3501 Terrace Street, Pittsburgh, PA, 15261, USA 9. Institute of Medical Science, Taipei Medical University, No. 250, Wuxing Street, Taipei, 110, Taiwan, ROC |
| Abstract: | Chalepensin, a furanocoumarin, is present in several medicinal Rutaceae plants and causes a mechanism-based inhibition of human and mouse cytochrome P450 (P450, CYP) 2A in vitro. To address the in vivo effect, we investigated the effects of chalepensin on multiple hepatic P450 enzymes in C57BL/6JNarl mice. Oral administration of 10?mg/kg chalepensin to mice for 7?days significantly decreased hepatic coumarin 7-hydroxylation (Cyp2a) and increased 7-pentoxyresorufin O-dealkylation (Cyp2b) activities, whereas activities of Cyp1a, Cyp2c, Cyp2e1, and Cyp3a were not affected. Without affecting its mRNA level, the decreased Cyp2a activity was accompanied by an increase in the immunodetected Cyp2a5 protein level. In chalepensin-treated mice, microsomal Cyp2a5 was less susceptible to ATP-fortified cytosolic degradation than that in control mice, resulting in the elevated protein level. The in vitro inactivation through NADPH-fortified pre-incubation with chalepensin also protected microsomal Cyp2a5 against protein degradation. Using cell-based reporter systems, chalepensin at a concentration near unbound plasma concentration activated mouse constitutive androstane receptor (CAR), in agreement with the observed induction of Cyp2b. These findings revealed that suicidal inhibition of Cyp2a5 and the CAR-mediated Cyp2b9/10 induction concurrently occurred in chalepensin-treated mice. |
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