Abstract
CYP3A4-mediated Phase I biotransformation is the rate-limiting step of elimination for many commonly used clinically agents. The modulatory effects of herbal medicines on CYP3A4 activity are one of the risk factors affecting the safe use of drug and herbal medicine. In the present study, the inhibitory effects of nearly hundred kinds of herbal medicines against CYP3A4 were evaluated based on a visual high-throughput screening method. Furthermore, biflavone components including bilobetin (7-demethylginkgetin, DGK), ginkgetin (GK), isoginkgetin (IGK), and amentoflavone (AMF) were identified as the main inhibitory components of Ginkgo biloba L. (GB) and Selaginella tamariscina (P. Beauv.) Spring (ST), which displayed very strong inhibitory effects toward CYP3A4. The inhibitory effects of these biflavones on clinical drugs that mainly undergo CYP3A4-dependent metabolism were evaluated. The IC 50 of GK toward tamoxifen, gefitinib and ticagrelor were found to be of 0.478 ± 0.003, 0.869 ± 0.001, and 1.61 ± 0.039 μM, respectively. These results suggest the potential pharmacokinetic interactions between the identified biflavones and clinical drugs undergoing CYP3A4-mediated biotransformation. The obtained information is important for guiding the rational use of herbal medicine in combination with synthetic pharmaceuticals.
Highlights
Cytochrome P450 (CYP) enzymes are a large class of heme-thiolate protein superfamily serving the key enzymes in the first-pass metabolism of many foreign substances in humans (Krishna and Shekar, 2005; Omura et al, 2005; Song et al, 2021)
The inhibitory effects of 93 herbal medicines toward CYP3A4 were preliminary evaluated using the high-throughput screening system constructed with CYP3A4 selective fluorescent probe NEN (Figure 1)
Inhibition of CYP3A4 by herbal medicine extracts was determined based of their effect on the intensity of fluorescence at 570 ± 15 nm that was excited at 488 nm
Summary
Cytochrome P450 (CYP) enzymes are a large class of heme-thiolate protein superfamily serving the key enzymes in the first-pass metabolism of many foreign substances in humans (Krishna and Shekar, 2005; Omura et al, 2005; Song et al, 2021). Among multiple CYP isoforms, CYP3A4 is mainly expressed in the liver and intestines of adult human, and has a wide substrate spectrum. CYP3A4 participates in the metabolic clearance of more than 50% of commonly used clinical drugs, including tyrosine kinase inhibitors, dihydropyridine calcium antagonists, benzodiazepines sedativehypnotics, and statins HMG-CoA reductase inhibitors (Niwa et al, 2008; van Waterschoot and Schinkel, 2011). CYP3A4 is the key enzyme in the metabolism of many commonly used drugs. It is regarded as one of the most important metabolic enzymes mediating the Phase I biotransformation.
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