Inhibitory effects of Hwang-Ryun-Hae-Dok-Tang on cytochrome P450 in human liver microsomes

Abstract

1. The herb–drug interaction potential of Hwang-Ryun-Hae-Dok-Tang (HR) extracts mediated by cytochrome P450 (CYP) inhibition was determined using human liver microsomes.

2. HR strongly inhibited CYP1A2 and moderately inhibited CYP2C19, CYP2D6, and CYP3A4 (testosterone) but not CYP2A6, CYP2B6, CYP2C8, CYP2C9, and CYP3A4 (midazolam).

3. The enzyme kinetic results suggest that CYP1A2 inhibition is competitively reversible (K_i, 13.4 ± 1.8 μg/ml), and CYP2D6 inhibition is quasi-irreversible (K_I, 0.234 ± 0.138 μg/ml; k_inact, 0.067 ± 0.006 min⁻¹).

4. Fermentation using Lactobacillus acidophilus attenuated the HR-induced inhibition of CYP2D6, but not the other isoforms.

5. Neither CYP1A2 nor CYP3A4 was markedly inhibited by berberine, palmatine, and geniposide—major components in HR—and CYP2D6 was inhibited by berberine (IC₅₀, 13.8 μg/ml) in a metabolism-dependent manner.

6. The results suggest the possibility of HR–drug interaction through inhibition of CYP—particularly CYP2D6—which may be attenuated by fermentation using L. acidophilus.

• Cytochrome P450
• fermentation
• herb–drug interaction
• Hwang-Ryun-Hae-Dok-Tang

Declaration of interest

This work was supported by a grant (No. K13050) from the Korean Institute of Oriental medicine (KIOM) funded by the Ministry of Education, Science, and Technology (MEST) and by a grant from the Korean Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A101836).