Abstract
BackgroundObtusofolin is the major active ingredient of Catsia tora L., which possesses the activity of improving eyesight and protecting the optic nerve. Investigation on the interaction of obtusofolin with cytochrome P450 enzymes (CYP450s) could provide a reference for the clinical application of obtusofolin.MethodsThe effect of obtusofolin on the activity of CYP450s was investigated in the presence of 100 μM obtusofolin in pooled human liver microsomes (HLMs) and fitted with the Lineweaver–Burk plots to characterize the specific inhibition model and kinetic parameters.ResultsObtusofolin was found to significantly inhibited the activity of CYP3A4, 2C9, and 2E1. In the presence of 0, 2.5, 5, 10, 25, 50, and 100 μM obtusofolin, the inhibition of these CYP450s showed a dose-dependent manner with the IC50 values of 17.1 ± 0.25, 10.8 ± 0.13, and 15.5 ± 0.16 μM, respectively. The inhibition of CYP3A4 was best fitted with the non-competitive inhibition model with the Ki value of 8.82 μM. While the inhibition of CYP2C9 and 2E1 was competitive with the Ki values of 5.54 and 7.79 μM, respectively. After incubating for 0, 5, 10, 15, and 30 min, the inhibition of CYP3A4 was revealed to be time-dependent with the KI value of 4.87 μM− 1 and the Kinact value of 0.0515 min− 1.ConclusionsThe in vitro inhibitory effect of obtusofolin implying the potential drug-drug interaction between obtusofolin and corresponding substrates, which needs further in vivo validations.
Highlights
Catsia tora Linn can be used as a food or medicine in traditional Chinese medicine, which possesses the activity of improving eyesight and protecting the optic nerve [1]
Cytochrome P450 enzymes (CYP450s) are a series of membrane-bound hemoproteins that participate in cellular metabolism and the biotransformation of numerous xenobiotics [8]
Obtusofolin significantly inhibited the activity of CYP3A4, 2C9, and 2E1 Corresponding inhibitors dramatically reduced the activity of all CYP isoforms (P < 0.05, Fig. 1)
Summary
Catsia tora Linn can be used as a food or medicine in traditional Chinese medicine, which possesses the activity of improving eyesight and protecting the optic nerve [1]. Obtusofolin is the major active ingredient of Catsia tora L. and has the effect of anti-oxidation [2]. The activity of CYP450s is a critical factor that may induce unfavorable interactions between various drugs. It is of great importance to evaluate the effect of different xenobiotics on the activity of major CYP450 isoforms. Obtusofolin is the major active ingredient of Catsia tora L., which possesses the activity of improving eyesight and protecting the optic nerve. Investigation on the interaction of obtusofolin with cytochrome P450 enzymes (CYP450s) could provide a reference for the clinical application of obtusofolin
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