Oxypeucedanin is a mechanism-based inactivator of CYP2B6 and CYP2D6

Background: Herbal medicine Angelica dahurica is widely employed for the treatment of rheumatism and pain relief in China. Oxypeucedanin is a major component of the herb. Objectives : The objectives of this study are aimed at the investigation of mechanism-based inactivation of CYP2B6 and CYP2D6 by oxypeucedanin, characterization of the reactive metabolites associated with the enzyme inactivation, and identification of the P450s participating in the bioactivation of oxypeucedanin. Methods : Oxypeucedanin was incubated with liver microsomes or recombinant CYPs2B6 and 2D6 under designed conditions, and the enzyme activities were measured by monitoring the generation of the corresponding products. The resulting reactive intermediates were trapped with GSH and analyzed by LC-MS/MS. Results : Microsomal incubation with oxypeucedanin induced a time-, concentration-, and NADPH-dependent inhibition of CYPs2B6 and 2D6 with kinetic values of KI/kinact 1.82 µM/0.07 min-1 (CYP2B6) and 8.47 µM/0.044 min-1 (CYP2D6), respectively. Ticlopidine and quinidine attenuated the observed time-dependent enzyme inhibitions. An epoxide and/or γ-ketoenal intermediate(s) derived from oxypeucedanin was/were trapped in microsomal incubations. CYP3A4 was the primary enzyme involved in the bioactivation of oxypeucedanin. Conclusion : Oxypeucedanin was a mechanism-based inactivator of CYP2B6 and CYP2D6. An epoxide and/or γ-ketoenal intermediate(s) may be responsible for the inactivation of the two enzymes.

Understanding the metabolism of the anticancer drug Triapine: electrochemical oxidation, microsomal incubation and in vivo analysis using LC-HRMS

The metabolism of the anticancer thiosemicarbazone Triapine was investigated.

Effect ofEclipta prostrataon 11Beta-Hydroxysteroid Dehydrogenase in Rat Liver and Kidney

Eclipta prostrata(EP) is often prescribed in combination with glucocorticoid to treat glomerular nephritis, nephrotic syndrome, and IgA nephropathy in clinical practice of Traditional Chinese Medicine. Previous studies from our laboratory revealed that coadministration of EP significantly increased the plasma concentration of prednisolone while decreased the level of cotreated prednisone in rats. However, the underlying mechanism remains unclear. 11β-Hydroxysteroid dehydrogenase (11β-HSD) belongs to the family of oxidoreductases that catalyze the interconversion of prednisone to active prednisolone. Therefore, the current study aimed to investigate the effects of EP on the activity and expression of 11β-HSD in rat liver and kidney. The results showed that oral administration of EP significantly increased the activity of 11β-HSD I in the liver and 11β-HSD II in the kidney by employing the microsomal incubation system. Moreover, gene and protein expressions of 11β-HSD I and 11β-HSD II were also increased in rat liver and kidney, respectively. These results suggest that the effects of EP on 11β-HSD may attribute to the mechanism that administration of EP improves the efficacy and reduces adverse drug reactions of glucocorticoid in patients undergoing combinational therapy.