KAMPO TODAY:Intestinal Bacteria Activate Glycosides in Crude Drugs

lycyrrhiza root is an important crude drug for Kampo and is used in about 70% of Kampo prescriptions. One of its possible active principles, glycyrrhizin, is a glycoside that combines two parts of glucuronic acid and one of glycyrrhetinic acid. Glycyrrhizin has many known effects, including anti-inflammatory, anti-allergic and steroid-like, and it is used in Japan today to treat hepatitis and allergies. However, its metabolism has been little studied, and much remains to be learned about the action on the human body of glycosides derived from crude drugs such as Glycyrrhiza root.

Akao et. al. at the Department of Hygiene of Toyama Medical and Pharmacological College undertook investigation of this subject based on the hypothesis that glycosides, which are present in many plants used in Kampo, become activated in the human body when they are broken down in water (hydrolyzed) by the action of glycosidase derived from bacteria in the human intestine. Examples of such glycosides include sennoside, which is the active principle of Rhubarb rhizome and accounts for its cathartic activity; paeoniflorin, which is the main constituent of Peony root and provides its sedative effect; and glycyrrhizin, which is referred to above.

Glycyrrhiza root, which has anti-inflammatory, anti-allergic and steroid-like effectiveness, is used in about 70% of Kampo Prescriptions.

When people or experimental animals are given glycyrrhizin orally, the compound is not detected in the blood serum. The serum contains glycrrhetinic acid, the aglycone from which the sugars of the administered compound have been removed. It has been assumed that since glycyrrhizin cannot be hydrolyzed by mammalian digestive enzymes, it is transformed into glycrrhetinic acid by the action of glycosidases from intestinal bacteria, which in turn is absorbed through the intestines.

Experiments were conducted with specific pathogen-free (SPF) rats and rats associated with human eubacterium sp. GLH. When glycyrrhizin was administered orally to SPF rats, it was not hydrolyzed, and no glycyrrhetinic acid (aglycone) was detected either in the blood or digestive tracts. However, when glycyrrhizin was given orally to SPF rats associated with human eubacterium sp GLH, they were found to have the same amount of glycyrrhetinic acid in the blood and digestive tracts as normal rats. Moreover, glycyrrhizin did not prevent liver damage induced experimentally in SPF rats by the administration of carbon tetrachloride. In contrast, glycyrrhizin did prevent such liver damage in SPF rats which were either given eubacterium sp GLH or allowed to gain a normal flora.

These results strongly suggest that orally-administered glycyrrhizin does not act by being directly absorbed and metabolized to glycyrrhetinic acid in the liver, but rather only after it is transformed into glycyrrhetinic acid by intestinal bacteria and then absorbed.

Glycyrrhizin and glycyrrhetinic acid, which is considered to be its active principle, were orally administered for the purpose of comparison. It was found that after administration of glycyrrhizin, the concentration of glycyrrhetinic acid in the blood slowly rose and reached its peak in 12 hours, maintained this level for 18 hours and then gradually declined. When glycyrrhetinic acid itself was given, however, its concentration in the blood rose higher and more promptly; the peak was twice as high and was reached within 3-4 hours before declining rapidly.

Active principle of Peony root, paeoniflorin, has sedative effect.

This finding may help explain why Kampo medicines have such a mild effect: they release active ingredients like glycyrrhetinic acid slowly and provide effective concentrations for an extended period without incurring the high concentrations that might provoke side effects. This contrasts with direct administration of glycyrrhetinic acid, which has been known to cause the side effect of pseudo-aldosteronism.

The most difficult task in analyzing Kampo medicines is the elucidation of the metabolism and absorption of their key components in order to help explain their therapeutic effect. This study, which focuses on the role of intestinal bacteria in the metabolism of important glycosides in Kampo, indicates one possible direction for gaining a better understanding of Kampo's action. In recognition of its significance, the study received an award from the Medical and Pharmacological Society for Wakan-Yaku at its 14th convention, which was held in Osaka on August 30-31 last year.