We have shown that the in vitro hepatic microsomal metabolism of pyranocoumarin compound decursinol angelate (DA) to decursinol (DOH) exclusively requires cytochrome P450 (CYP) enzymes, whereas the conversion of its isomer decursin (D) to DOH can be mediated by CYP and esterase(s). To provide insight into specific isoforms involved, here we show with recombinant human CYP that 2C19 was the most active at metabolizing D and DA in vitro followed by 3A4. With carboxylesterases (CES), D was hydrolyzed by CES2 but not CES1, and DA was resistant to both CES1 and CES2. In human liver microsomal (HLM) preparation, the general CYP inhibitor 1-aminobenzotriazole (ABT) and respective competitive inhibitors for 2C19 and 3A4, (+)-N-3-benzylnirvanol (NBN) and ketoconazole substantially retarded the metabolism of DA and, to a lesser extent, of D. In healthy human subjects from a single-dose pharmacokinetic (PK) study, 2C19 extensive metabolizer genotype (2C1917 allele) tended to have less plasma DA AUC0-48h and poor metabolizer genotype (2C192 allele) tended to have greater DA AUC0-48h. In mice given a single dose of D/DA, pretreatment with ABT boosted the plasma and prostate levels of D and DA by more than an order of magnitude. Taken together, our findings suggest that CYP isoforms 2C19 and 3A4 may play a crucial role in the first pass liver metabolism of DA and, to a lesser extent, that of D in humans. Pharmacogenetics with respect to CYP genotypes and interactions among CYP inhibitor drugs and D/DA should therefore be considered in designing future translation studies of DA and/or D.
Bibliographical noteFunding Information:
This work was supported, in part, by National Center for Complementary and Integrative Health (NCCIH/NCCAM) R01 grant AT007395 and TTUHSC School of Pharmacy start-up fund (J.L.), and Laura W. Bush Institute for Women’s Health Seed Grant (J.Z.). The authors thank the School of Pharmacy Faculty member Dr. Reza Mehvar for helpful discussions, Ms. Kito Barrow and Ms. Vi Bui for technical assistance and Michael Melkus, Ph.D., for help with editing the English text.
© 2015 World Scientific Publishing Company & Institute for Advanced Research in Asian Science and Medicine.
- Angelica gigas Nakai
- Cytochrome P450
- Decursinol Angelate