Chemistry

When we think of licorice, we typically think of the popular candy. Licorice, however, has an important history in herbal medicine. Licorice is a perennial shrub that is indigenous to the Mediterranean and is cultivated in the Middle East, Spain, northern Asia, and the United States. The most common variety used for medicinal purposes is Glycyrrhiza glabra var. typica. Licorice has been used since Roman times and was described in early Chinese writings.

The root and rhizomes of the licorice plant contain —5% to 9% of a steroidal glycoside called glycyrrhizin (Fig. 29.19). In the glycoside form, glycyrrhizin is 150 times sweeter than sugar. Also present are triterpenoids, glucose, mannose, and sucrose. Concentrated aqueous extracts may contain 10% to 20% glycyrrhizin. When the herb is ingested, the intestinal flora catalyze the conversion of glycyrrhizin into gly-cyrrhetic acid (Fig. 29.19), the pharmacologically active

Glycyrrhetic Acid R-| = H Glycyrrhizin R1 = R'

Figure 29.19 • Chemical components of licorice.

Glycyrrhetic Acid R-| = H Glycyrrhizin R1 = R'

compound. Glycyrrhizin and glycyrrhetic acid possess mild anti-inflammatory properties. Glycyrrhizin appears to stimulate gastric mucus secretion. This may be the origin of the antiulcer properties of licorice. Glycyrrhizin and gly-cyrrhetic acid do not act directly as steroids. Instead, they potentiate, rather than mimic, endogenous compounds.

There is some interesting folklore relating to the use of licorice. During World War II, a Dutch physician73 noticed that patients with peptic ulcer disease improved dramatically when treated with a paste containing 40% licorice extract. The physician treated many patients in this way, but during the course of his work, he noticed that there was a serious side effect from the herbal drug. About 20% of his ulcer patients developed a reversible edema of the face and extremities. Since these original observations, many studies have been conducted with licorice root. The findings have remained the same; licorice is useful for peptic ulcer disease, but potentially serious mineralocorticoid side effects are possible (lethargy, edema, headache, sodium and water retention, excess excretion of potassium, and increased blood pressure).

Licorice exerts its protective effects on the gastric mucosa by inhibiting two enzymes, 15-hydroxyprostaglandin dehydrogenase and A13-prostaglandin reductase. Inhibition of these enzymes causes their substrates to increase in concentration, increasing the levels of prostaglandins in the gastric mucosa and causing a cytoprotective effect. The acid also inhibits 11-^-hydroxysteroid dehydrogenase,74 thus increasing the glucocorticoid concentration in mineralocorti-coid-responsive tissues, causing increased sodium retention, potassium excretion, and blood pressure.

In the 1960s, a semisynthetic compound based on gly-cyrrhetic acid, 4-O-succinylglycyrrhetic acid (carbenox-olone), was introduced in Europe. It proved effective against peptic ulcer disease, but it was later shown to be inferior to the H2-receptor antagonists.

Licorice is also an effective demulcent, soothing a sore throat, and is an expectorant and cough suppressant.

Licorice can cause serious adverse reactions. These are mineralocorticoid effects (pseudoprimary aldostero-nism), muscle weakness, rhabdomyolysis, and heart failure. Poisoning by licorice is insidious. Long-term high doses are extremely toxic. Licorice can potentiate the digitalis glycosides and cause toxicity. With cardiovascular agents that prolong the QT interval, the effects may be additive.

# REVIEW QUESTIONS^

1. What did the Durham-Humphrey Amendment do to drug commerce?

2. What enzyme is induced by St. John's wort and is responsible for prescription drug interactions with this herb?

3. What drug interaction is commonly observed with G. biloba use?

4. What is the most problematic aspect of herbal manufacture in the United States?

5. What is the constituent of St. John's wort that is now believed to be responsible for the antidepressant effect of the herb?

6. What herbal drug has been shown to be an effective hepatoprotectant?

7. What herbal drug is an effective treatment for peptic ulcers, albeit with unfortunate side effects?

8. What is a rhizome?

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