Modulatory Effects of Atractylodin and β-Eudesmol on Human Cytochrome P450 Enzymes: Potential Drug-Drug Interactions

Abstract

Atractylodin and β-eudesmol, the major bioactive compounds in Atractylodes lancea, are promising candidates for anti-cholangiocarcinoma. The inhibitory effects of both compounds on human rCYP1A2, rCYP2C9, rCYP2C19, rCYP2D6 and rCYP3A4 enzymes were investigated using luminogenic CYP450 kits. The modulatory effects were investigated in mouse livers following a daily oral dose of atractylodin or β-eudesmol at 100 mg/kg body weight for 1, 7, 14, and 21 days. The inhibitory effects of both compounds on all rCYP450s were weak (IC50: 167 to >686 µM). β-Eudesmol showed the most potent inhibitory effect on rCYP2C19 (IC50 = 172.7 µM) and rCYP3A4 (IC50 = 218.6 µM). Results of the ex vivo study showed that short exposure (1–7 days) of atractylodin and β-eudesmol resulted in the upregulation of mRNA. Prolonged exposure to the daily oral dose for at least 14 days significantly downregulated the expressions of mRNA and proteins, which correlated with the decrease in the activities of mCYP1A2 and mCYP3A11. Based on the results of the ex vivo study, clinical uses of atractylodin or β-eudesmol for the treatment of cholangiocarcinoma are of concern for the risk of toxicity due to hCYP3A4 inhibition following chronic dosing, as well as the metabolic interaction with the coadministered drugs that are metabolized by hCYP3A4.

The roles of CYP2C19 and CYP3A4 in the in vitro metabolism of β‐eudesmol in human liver: Reaction phenotyping and enzyme kinetics

“…The CYP modulatory activities of the AL and its major active compounds, atractylodin, and β‐eudesmol, have been investigated both in vitro and in vivo. 13 , 14 , 15 Nevertheless, there is currently no available study that identifies the specific CYP enzyme(s) responsible for the metabolism of AL or its major constituents. This knowledge gap motivated our study to investigate the metabolizing enzyme(s) involved in AL metabolism using β‐eudesmol as the marker compound due to its relatively high quantity (6%) and stability at body temperature (Table S1 ).…”

“…Our earlier research showed that β‐eudesmol acts as an inhibitor of rCYP2C19 and rCYP3A4. 15 This may suggest that β‐eudesmol might have a dual role, functioning both as an inhibitor and a substrate for these CYP enzymes. In another previous study involving ligand‐binding spectroscopy of rCYPs prepared using Escherichia coli membrane, considerable binding of β‐eudesmol to CYP1A2 and CYP3A4, but not CYP2C9, CYP2C19, and CYP2D6 were reported.…”

“… 14 Similarly, in mice, the active constituents of AL, atractylodin and β‐eudesmol, were found to inhibit CYP1A2 and CYP3A11 following prolonged daily administrations of 100 mg/kg body weight for 14 days. 15 However, β‐eudesmol has demonstrated inhibitory effects on rCYP2C19 and rCYP3A4 in vitro. 15 …”