From cholesterol to oxysterols. Current data

Abstract

Oxysterols, a class of cholesterol oxidation products exhibit several important biological activities. Some of these natural compounds are potent inhibitors of the enzyme HMG-CoA reductase, a key enzyme in the cholesterol biosynthetic pathway. Many studies have been directed towards to the verification of the hypothesis that some oxysterols are endogenous intracellular regulators of cholesterol homeostasis. In adition to oxysterols derived directly from oxidation of cholesterol, several others are formed from squalene dioxide. It is presently well established that, in addition to the classical cholesterol biosynthetic pathway, there exists an alternate bifurcation from squalene oxide. The cyclisation of squalene dioxide leads to a series of new oxysterols. Thus, several types of oxysterols and several molecular targets are involved in the regulation of steroid biosynthesis. Many oxysterols, particularly those obtained from the oxidations of phytosterols and tetracyclic triterpenes are potent cytotoxic agents. They are selectively cytotoxic against tumorous cells. This cytotoxicity depends markedly on the specific structure of each oxysterol. Some structures are very cytotoxic, while their stereoisomers are inactive. The activity depends on the tumor cells which are used in the assay system: some compounds display inhibitory activity towards hepatoma cells but are inactive against lymphoma cells while others act in the opposite manner. Free oxysterols do not depress tumor growth in living animals. However, several water soluble prodrugs of oxysterols are able to depress different type of tumors in vivo. Clinical trial studies are presently conducted in order to learn the therapeutic values of these oxysterols.