Research progress on the protective effects of licorice-derived 18ß-glycyrrhetinic acid against liver injury.

The first description of the medical use of licorice appeared in "Shennong Bencao Jing", one of the well-known Chinese herbal medicine classic books dated back to 220-280 AD. As one of the most commonly prescribed Chinese herbal medicine, licorice is known as "Guo Lao", meaning "a national treasure" in China. Modern pharmacological investigations have confirmed that licorice possesses a number of biological activities, such as antioxidation, anti-inflammatory, antiviral, immune regulation, and liver protection. 18ß-glycyrrhetinic acid is one of the most extensively studied active integrants of licorice. Here, we provide an overview of the protective effects of 18ß-glycyrrhetinic acid against various acute and chronic liver diseases observed in experimental models, and summarize its pharmacological effects and potential toxic/side effects at higher doses. We also make additional comments on the important areas that may warrant further research to support appropriate clinical applications of 18ß-glycyrrhetinic acid and avoid potential risks.

Modulation of Cytochrome P450 Activity by 18ß-Glycyrrhetic Acid and its Consequence on Buspirone Pharmacokinetics in Rats.

The aim of this study was to elucidate the inhibition mechanism of 18ß-glycyrrhetic acid (GLY) on cytochrome P450 (CYP) activity and in vivo pharmacokinetic consequences of single GLY dose in rats. An in vitro CYP inhibition study in rat liver microsomes (RLM) was conducted using probe substrates for CYPs. Then, an in vivo pharmacokinetics of intravenous and oral buspirone (BUS), a probe substrate for CYP3A, was studied with the concurrent administration of oral GLY in rats. In the in vitro CYP inhibition study, CYP3A was involved in the metabolism of GLY. Moreover, GLY inhibited CYP3A activity with an IC50 of 20.1 ± 10.7 µM via a mixed inhibition mechanism. In the in vivo rat pharmacokinetic study, single oral GLY dose enhanced the area under plasma concentration-time curve (AUC) of intravenous and oral BUS, but the extent of increase in AUC was only minimal (1.12-1.45 fold). These results indicate that GLY can inhibit the in vitro CYP3A-mediated drug metabolism in RLM via a mixed inhibition mechanism. However, the impact of single oral GLY dose on the pharmacokinetics of BUS in rats was limited, showing that GLY could function as merely a weak inhibitor for CYP3A-mediated drug metabolism in vivo. Copyright © 2015 John Wiley & Sons, Ltd.

Hyperpolarization-Activated Cyclic Nucleotide-Gated Non-selective (HCN) Ion Channels Regulate Human and Murine Urinary Bladder Contractility.

Purpose: Hyperpolarization-activated cyclic nucleotide gated non-selective (HCN) channels have been demonstrated in the urinary bladder in various species. Since they play a major role in governing rhythmic activity in pacemaker cells like in the sinoatrial node, we explored the role of these channels in human and murine detrusor smooth muscle. Methods: In an organ bath, human and murine detrusor smooth muscle specimens were challenged with the HCN channel blocker ZD7288. In human tissue derived from macroscopically tumor-free cancer resections, the urothelium was removed. In addition, HCN1-deficient mice were used to identify the contribution of this particular isoform. Expression of HCN channels in the urinary bladder was analyzed using histological and ultrastructural analyses as well as quantitative reverse transcriptase polymerase chain reaction (RT-PCR). Results: We found that the HCN channel blocker ZD7288 (50 µM) both induced tonic contractions and increased phasic contraction amplitudes in human and murine detrusor specimens. While these responses were not sensitive to tetrodotoxin, they were significantly reduced by the gap junction inhibitor 18ß-glycyrrhetic acid suggesting that HCN channels are located within the gap junction-interconnected smooth muscle cell network rather than on efferent nerve fibers. Immunohistochemistry suggested HCN channel expression on smooth muscle tissue, and immunoelectron microscopy confirmed the scattered presence of HCN2 on smooth muscle cell membranes. HCN channels seem to be down-regulated with aging, which is paralleled by an increasing effect of ZD7288 in aging detrusor tissue. Importantly, the anticonvulsant and HCN channel activator lamotrigine relaxed the detrusor which could be reversed by ZD7288. Conclusion: These findings demonstrate that HCN channels are functionally present and localized on smooth muscle cells of the urinary bladder. Given the age-dependent decline of these channels in humans, activation of HCN channels by compounds such as lamotrigine opens up the opportunity to combat detrusor hyperactivity in the elderly by drugs already approved for epilepsy.