A drug over the millennia: Pharmacognosy, chemistry, and pharmacology of licorice

Licorice, the root of Glycyrrhiza spp. (Fabaceae), has been used since anci ent Egyptian; Greek, and Roman times in the West and since the Former I-lan era (the 2nd-3rd century B.C.) in ancient China in the East. In traditiona l Chinese medicine, licorice is one of the most frequently used drugs. In J apan, the oldest specimen of licorice introduced from China in the middle o f the 8th century still exists in Shosoin, the Imperial Storehouse, in Nara . Extracts of licorice were recommended as a remedy for gastric ulcer by Re vers of the Netherlands in 1946, which was soon withdrawn owing to its side effects. Carbenoxolon sodium, glycyrrhetinic acid (GA) hemisuccinate Na, w as prepared from licorice to treat peptic ulcer in the UK. In Japan for the past 60 years, a glycyrrhizin (GL) preparation under the name of Stronger Neo-Minophagen C (SNMC) has been used clinically as an antiallergic and ant ihepatitis agent. GL and GA sometimes induce edema, hypertension, and hypok alemia in patients treated with higher doses and long-term administration. The mechanism of this side effect, pseudoaldosteronism, has been explained as due to the Il-hydroxy-steroid dehydrogenase inhibitory activity of GL an d GA. The excess of endogenous cortisol produced combines with the renal mi neral corticoid receptor, which promotes an aldosterone-like action. GL and GA reduce alanine transaminase (ALT) and aspartate transaminase (AST) valu es in the serum. This hepatoprotective effect has recently been explained a s the inhibitory effects of GL and GA on immune-mediated cytotoxicity again st hepatocytes and on nuclear factor (NF)-kappa B, which activates genes en coding inflammatory cytokines in the liver. To exclude the side effects and enhance the therapeutic activities, chemical modification of GL and GA has been performed. Deoxoglycyrrhetol (DG), homo- and heteroannular diene homo logs of dihemiphthalates, showed a remarkable improvement in antiinflammato ry, antiallergic, and antiulcer activities in animal experiments. Immunomod ulating effects of GL, GA, and DG derivatives, which induce interferon-gamm a and some other cytokines, have been demonstrated in relation with their a ntiviral activities. Antiinflammatory, antitumorigenic, and antimalarial ef fects of licorice flavonoids have also been investigated.