Water soluble nortropane alkaloids in crude drugs, edible fruits and vegetables: biological activities and therapeutic applications

The tropane alkaloids are a well-recognized group of structurally related natural products and have long been known to have anticholinergic, antiemetic, parasympatholytic, anesthetic, and many other actions. This class of alkaloid includes such important medicinal alkaloids as cocaine, scopolamine, and atropine. In 1988, polyhydroxylated nor tropane alkaloids were discovered as plant metabolic mediators in the rhizosphere from Calystegia sepium (Convolvulaceae) and given the trivial names calystegines (Tepfer et al., 1988). In the course of isolation of 1-deoxynojirimycin from mulberry plants, we found calystegines B 2 and C 1 , and that these compounds had potent glycosidase inhibitory activity (Asano et al., 1994a,b). This prompted us to search for other calystegines from a wide range of plants. The genera Atropa, Datura, Duboisia, Hyoscyamus, and Scopolia, which belong to the Solanaccae, are especially rich sources of tropane alkaloids. Calystegines have now been found in all these genera and even in most genera of the Solanaceae (Molyneux et al., 1996; Nash et al., 1996). Surprisingly, a traditional Chinese crude drug 'Ti-koppi', which is the root barks of Lycium chinense (Solanaceae), contained many kinds of calystegines such as calystegines A 3 ,A 5 , A 6 , A 7 , B 1 , B 2 , B 3 , B 4 , B 5 , C 1 , C 2 , N and N-methyl-calystegines B 2 and C, (Asano et al., 1997a). Some calystegines are potent inhibitors of β-glucosidase and α-galactosidase with IC 50 values ranging 10 -6 -10 7 M. There are many edible fruits and vegetables in the families Solanaceae and Convolvulaceae. A particularly interesting aspect of the biological activity of calystegines is their potential toxicity toward humans which ingest them. It is possible that the calystegines, which inhibit β-glucosidase and α-galactosidase, might produce syndromes that mimic a genetic deficiency of such activities, namely, Gaucher and Fabry diseases, respectively. We surveyed the occurrence of calystegines in edible fruits and vegetables, and detected some of calystegines A 3 , B 1 , B 2 , and C 1 or all from all samples in the Solanaceae and Convolvulaceae tested (Asano et al., 1997b). The presence of calystegines in human foods such as tomatoes, potatoes, eggplants, and sweet potatoes poses the question as to the effect that these compounds might have on humans. Although calystegines B 1 and C 1 potently inhibited human liver lysosomal β-glucosidase, preliminary experiments have indicated that they do not cause additional lysosomal storage in human fibroblasts in culture for 1 week in the presence of 1 mM of the calystegine. Interestingly, a quite recent work indicates that calystegine B 2 , which is a good inhibitor of human lysosomal α-galactosidase A (a-Gal A) with an IC 50 value of 30 μM, enhances the enzyme activity in lymphoblasts derived from Fabry patients with the R301Q mutation identified in cardiac Fabry patients. The enzyme activity was increased fivefold by cultivation with calystegine B 2 at 1 mM.