GLYCOSIDES

2011

Glycosides consist of any of the many other categories of secondary metabolites discussed here that are bound to a monosaccharide or an oligosaccharide, or to uronic acid. The saccharide or uronic acid portion is referred to as the glycone, and whatever other molecule the glycone is attached to is referred to as the aglycone. For example, flavonoids frequently occur as glycosides, in which case, the flavonoid is the aglycone and whatever saccharide it is attached to is the glycone. The glycone and aglycone are attached via a glycosidic linkage. Although this usually involves a covalent bond to oxygen, it can also involve carbon, nitrogen, or sulfur, depending on the aglycone.

Because of the diversity of aglycones and glycosides, these compounds do not share a common biosynthetic pathway. The process of forming the glycosidic linkage is known as glycosylation and is accomplished via specialized enzymes that use a uridine diphosphosugar as the glycone source. The addition of the glycone usually renders the total glycoside more polar and thus more water soluble than the isolated aglycone. In most instances, it is believed that glycosides are formed to enhance ease of movement and storage of nonpolar or weakly polar aglycones within the plant.

The glycosidic linkage is relatively fragile. Several enzymes exist that can break the link, including beta-glu-cosidase and beta-galactosidase. It is unclear whether these enzymes exist in the gastrointestinal lumen of most animals but they almost always occur in their livers. Gut flora also typically possess these enzymes. Heat can break the bonds. According to one study of glycoside breakdown in leaves of Senna alexandrina (senna), 30° C (86° F) and 60% relative humidity and 40° C (104° F) and 75% relative humidity were sufficient to cause significant glycoside loss compared with 25° C (77° F) and 60% relative humidity. A methanol extract of senna showed much less breakdown except at even higher temperatures. Ultraviolet light and extremes of pH can also break some of these bonds. Because of the changes in pharmacokinetics and possibly pharmacodynamics of herbs with intact glycosides versus free aglycones, many botanical practitioners believe that it is important for herbs containing glycosides to undergo minimal processing.

The pharmacokinetics of glycosides are complex but central to an understanding of their importance. A simple model is that of a built-in delayed release system, in which the hydrophilic glycoside delivers a hydrophobic aglycone to the large intestines. Most intact glycosides generally pass through the stomach and small intestines unchanged. However, some glycosides are absorbed, apparently by the intestinal epithelial intestinal Na+/ glucose monosaccharide cotransporter, SGLT-1.

Once in the colon, the glycosidic bond is hydrolyzed by enzymes possessed by the gut flora. Some aglycones released by this process may also undergo enzymatic modification by gut bacteria. Aglycones are then absorbed via the large intestine, undergo first-pass metabolism in the liver, and circulate to varying degrees within the body. This process has been extensively studied, for example, with the glycosides in Panax ginseng (Asian ginseng) roots, known as ginsenosides. Ginsenoside aglycones released by the action of gut flora have been shown to be more potent antineoplastic compounds compared with intravenously injected intact ginsenosides in mice. Some ginsenosides are esterified to fatty acids in the liver and may have prolonged half-lives as a result.

Other properties of glycosides are highly dependent on the specific aglycone present. Some important types of glycosides are discussed in the following section to give the reader a sense of the wide range of therapeutic applications they can have.

Cardiac Glycosides

Anthraquinone Glycosides

Cyanogenic Glycosides

Cyanogenic glycosides have amino acid-derived aglycones that are mostly a safety concern in medicinal plants. The concerns about cyanogenic glycosides are twofold. First, these compounds interfere with iodine organification and thus can cause or promote goiter and hypothyroidism. However, this problem has been clearly documented to occur only in the setting of iodine deficiency or with massive overconsumption. Second, cyanogenic glycosides do spontaneously degrade to release potentially lethal hydrogen cyanide once the glycosidic linkage is hydrolyzed. However, unless massive and rapid intake of cyanogenic glycosides occurs, the cyanide is quickly and safely detoxified by hepatic thiosulfate sulfurtransferase. Smaller animals, juveniles, and herbivores that eat large amounts of Prunus spp leaves or white clover are potentially more susceptible. Other symptoms of acute cyanide exposure include headache, bronchial constriction, and weakness. Toxic effects, if any, of chronic, low-level exposure are unknown.

Evidence suggests that cyanogenic glycosides may have beneficial effects in animals that consume them. The most controversial evidence involves the cyanogenic glycosides from Prunus spp (cherry), particularly amygdalin (sold under the trade name Laetrile) and prunasin. These compounds do have anticarcinogenic activity in vitro according to recent research. Previous animal and human studies have, however, failed to show convincing clinical effectiveness of isolated injections of amygdalin. Prunasin has also been shown to inhibit DNA polymerase in vitro.