Abstract
Ginsenoside compound K (CK), a rare ginsenoside originating from Panax Ginseng, has been found to possess unique pharmacological activities specifically as anti-cancers. However, the role of cytochrome P450s (CYPs) in the metabolism of CK is unclear. In this study, we screened the CYPs for the metabolism of CK in vitro using human liver microsomes (HLMs) or human recombinant CYPs. The results showed that CK inhibited the enzyme activities of CYP2C9 and CYP3A4 in the HLMs. The Km and Vmax values of CK were 84.20±21.92 μM and 0.28±0.04 nmol/mg protein/min, respectively, for the HLMs; 34.63±10.48 μM and 0.45±0.05 nmol/nmol P450/min, respectively, for CYP2C9; and 27.03±5.04 μM and 0.68±0.04 nmol/nmol P450/min, respectively, for CYP3A4. The IC50 values were 16.00 μM and 9.83 μM, and Ki values were 14.92 μM and 11.42μM for CYP2C9 and CYP3A4, respectively. Other human CYP isoforms, including CYP1A2, CYP2A6, CYP2D6, CYP2E1, and CYP2C19, showed minimal or no effect on CK metabolism. The results suggested that CK was a substrate and also inhibitors for both CYP2C9 and CYP3A4. Patients using CK in combination with therapeutic drugs that are substrates of CYP2C9 and CYP3A4 for different reasons should be careful, although the inhibiting potency of CK is much poorer than that of enzyme-specific inhibitors.
Highlights
Panax Ginseng is a complementary and alternative medicine (CAM) that has many pharmacological activities, such as maintaining physical vitality and boosting resistance to stress and aging [1]
In the presence of sulfaphenazole and ketoconazole, the metabolic clearance rate (MCR) of compound K (CK) decreased to 73.5±20.9% and 74.6±28.1% of that of the control, respectively (Fig 3)
The screened enzymes were further confirmed by human recombinant cytochrome P450s (CYPs) using the specific inhibitors
Summary
Panax Ginseng is a complementary and alternative medicine (CAM) that has many pharmacological activities, such as maintaining physical vitality and boosting resistance to stress and aging [1]. The main constituents comprising more than 80% of the content of Panax Ginseng are Rb1, Rb2, Rc, Rg1, and Re. The rest are known as rare ginsenosides, which account for only a small portion of the total saponins, and they have unique pharmacological activities [4]. Ginsenoside compound K (CK), or 20-O-β-(D-glucopyranosyl)-20(S)-protopanaxadiol (The molecular structure is shown in Fig 1), is naturally absent. It belongs to the rare ginsenoside, which is transformed from ginsenosideRb1 and Rb2 by intestinal bacteria [5]. CK increases the resistance to immunity function to extend the transplant survival time in heart transplantation, has an anti-inflammatory function, resists skin aging, and protects the myocardium [1, 8]
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