RT Journal Article
SR Electronic
T1 Imperatorin Is a Mechanism-Based Inactivator of CYP2B6
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 82
OP 88
DO 10.1124/dmd.114.060558
VO 43
IS 1
A1 Liwei Zheng
A1 Jiaojiao Cao
A1 Dan Lu
A1 Lin Ji
A1 Ying Peng
A1 Jiang Zheng
YR 2015
UL http://dmd.aspetjournals.org/content/43/1/82.abstract
AB Imperatorin (IMP) is the major active ingredient in many common medicinal herbs. We examined the irreversible inhibitory effect of IMP on CYP2B6. IMP produced a time- and concentration-dependent inactivation of CYP2B6. About 70% of activity of CYP2B6 was suppressed after its incubation with 1.5 μM IMP for 9 minutes. KI and kinact were found to be 0.498 μM and 0.079 min−1, respectively. The loss of CYP2B6 activity required the presence of NADPH. Glutathione and catalase/superoxide dismutase showed little protection against the IMP-induced enzyme inactivation. Ticlopidine, a substrate of CYP2B6, showed protection of the enzyme against the inactivation induced by IMP. The estimated partition ratio of the inactivation was approximately 4. Additionally, a γ-ketoenal intermediate was identified in microsomal incubations with IMP. CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 were found to be involved in bioactivation of IMP. In conclusion, IMP is a mechanism-based inactivator of CYP2B6. The formation of γ-ketoenal intermediate may account for the enzyme inactivation