In vitro and in vivo Inhibitory Effects of Glycyrrhetinic Acid on Cytochrome P450 3A Activity

Abstract

The liquorice plant has long been used in both Eastern and Western cultures. Glycyrrhizin is the major triterpenoid saponin in liquorice root, and glycyrrhetinic acid (GA) is its predominant metabolite and a pharmacologically active form of glycyrrhizin. We have assessed the ability of GA to inhibit the enzyme cytochrome P450 3A (CYP3A). A Lineweaver-Burk plot showed that GA was a mixed inhibitor of CYP3A, with an IC₅₀ of 7.25 µmol/l, a K_m of 4.3 µmol/l and a K_i of 6.4 µmol/l by non-linear regression analysis. CYP3A activity was also affected by intragastric administration of GA, which resulted in increases in area under the plasma concentration-time curve (AUC)_0–t and in apparent elimination half-time (t_1/2) and significant decreases in body clearance, as well as in the formation of 1-hydroxy-midazolam after intragastric or intravenous administration of midazolam (p < 0.05). An increase in C_max after intragastric administration (p < 0.05) was also observed. These results suggest the likelihood of an interaction between GA and CYP3A-metabolised drugs in humans and indicate that liquorice root should be used with caution when taken concomitantly with other drugs that interact with CYP3A.

Glycyrrhetinic acid might increase the nephrotoxicity of bakuchiol by inhibiting cytochrome P450 isoenzymes

“…Our results showed that GA inhibited the activities of CYP1A2, CYP2C9 and CYP3A4 in HLMs, and the IC 50 values of GA for CYP2C9, CYP3A4, and CYP2D6 were similar to those reported in other studies (Li et al, 2010; Liu et al, 2011). The results indicated that GA strongly inhibited CYP3A4 and weakly inhibited CYP2C9 and CYP1A2.…”

“…CYP isozymes can be inhibited or induced by drugs, resulting in drug-drug interactions that can cause adverse reactions or reduce the effectiveness of therapies (Baillie, 2007; Ioannides, 2008; Choi, Chin & Kim, 2011). As the active metabolite of the main component in licorice, GA has been shown to modulate various CYP isoforms (Li et al, 2010; Liu et al, 2011), suggesting its potential to cause metabolic interactions.…”

“…GA is absorbed in blood as the active metabolite of licorice. GA inhibited the activities of cytochrome P450 isozymes, such as CYP2C9, CYP2C19 and CYP3A4 (Li et al, 2010; Liu et al, 2011), which are involved in the metabolic detoxification of BAK. We hypothesized that GA may increase the toxicity of BAK by inhibiting its detoxification enzymes CYP450s.…”

Interactions between Herbs and Conventional Drugs: Overview of the Clinical Data

“…However, both glycyrrhizin and glycyrrhetic acid (i.e. chemical components of licorice) have recently been shown to induce CYP3A4 in humans [119,120]. In the absence of definitive data for standardized licorice extracts, it is suggested that this herbal remedy should be used with caution when taken concomitantly with other drugs that interact with CYP3A4.…”

Toxicological Effects of Glycyrrhiza glabra (Licorice): A Review

“…The licorice root‐derived isoflavan (glabridin) showed inhibitory effects on CYP3A4, 2B6, and 2C9 (Kent et al ., ). In vitro and in vivo , glycyrrhetinic acid shows inhibitory effects on CYP3A (Li et al ., ; Liu et al ., ; Lv et al ., ), 2C9, and 2C19 enzymes (Liu et al ., ; Lv et al ., ). However, former studies showed that prolong intake of licorice and glycyrrhizin induces CYP isoenzyme activity on rodent liver (Paolini et al ., ; Paolini et al ., ) that are proved using Vivid CYP450 Screening Kits (Hou et al ., ) and human study (Tu et al ., ).…”