Inhibition of glucocerebrosidase and induction of neural abnormality by cyclophellitol in mice

Abstract

Cyclophellitol, a cyclitol with an epoxide, is a novel microbial secondary metabolite that inhibits beta-glucosidase and beta-glucocerebrosidase. Daily administration of cyclophellitol induces a severe abnormality of the nervous system in mice while it has no toxicity in various cultured cells. It was shown to inhibit glucocerebrosidase in vivo significantly in mice and the content of glucocerebroside in liver, spleen, and brain was increased markedly. The enzyme activity was completely suppressed in brain, liver, spleen, kidney, and muscle. On the other hand hexosaminidase activity was not affected in all tissues. After a single administration of cyclophellitol the maximal inhibition of glucocerebrosidase was observed within 30 min in brain and liver, and the inhibition lasted for 2-4 days. A single administration of cyclophellitol also induced a severe abnormality of the nervous system known as Gaucher's-like disease in mice. Conduritol B epoxide is also known to inhibit glucocerebrosidase and induce Gaucher's like-disease in mice by repetitive injection. Cyclophellitol was shown to be more potent than conduritol B epoxide in inhibition of glucocerebrosidase and in induction of the neural abnormality.