Investigations on the mechanism of the hypocholesterolemic action of 1-ethoxysilatrane

Abstract

Intraperitoneal administration of the nontoxic silicon compound, 1-ethoxysilatrane, to the rat did not cause proliferation of hepatic mitochondria or of endoplasmic reticulum, nor did it affect mitochondrial oxidative phosphorylation. The activities of cholesterol 7 alpha-hydroxylase in hepatic microsomes and of cholesterol oxidase in mitochondria respectively were unaffected by silatrane treatment. The rate of release of bile, whose composition remained unchanged, also was not increased in silatrane-treated animals. The results indicated that the compound did not affect the pathway of cholesterol degradation. A progressive decrease in the activity of hepatic microsomal 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase was observed on administration of the compound over a period of three weeks. Consistent with this, cholesterol biosynthesis in liver as measured by incorporation of radioactive precursors, acetate and water but not mevalonate, was significantly decreased in silatrane-treated animals. However, enzyme-linked immunosorbent assay revealed that the concentration of HMGCoA reductase protein was not decreased by the treatment indicating that inactivated enzyme was also present in such microsomes. Addition of silatrane to microsomes in the assay system did not cause inhibition indicating that the inactivation is by an indirect mechanism. It is concluded that the hypocholesterolemic action of the compound rested entirely on the inhibition of cholesterol biosynthesis in vivo by inactivation of the rate-limiting enzyme HMGCoA reductase.

Preparation of a soluble 58kDa-3-hydroxy-3-methylglutaryl CoA reductase from liver microsomes and its inhibition by ethoxysilatrane, a hypocholesterolemic compound

“…It is also of interest to mention that a preparation of an active 58 kDa-enzyme was obtained from a cDNA clone of the human HMGCoA reductase in E. coli which is dimeric and much less cold labile than the 50 kDa-enzyme [28]. It had been reported [12] that in the silatrane-administered animals the enzyme was inactivated but the protein was retained. The results presented in this paper indicate that the inactivation by silatrane is reversible with no apparent involvement of a chemical reaction.…”

“…Clofibrate [7], cholesterol [13], deithylhexylphthatate [10] and silatrane [12] may be cited as examples. Experiments in our laboratory have indicated that these agents fail to inhibit the activity even when microsomal membrane organization is sought to be perturbed with detergents.…”

“…A number of compounds given to rats are known to decrease the concentration in serum and biogenesis in the liver, of cholesterol. Some examples are ~x-p-chlorophenoxyisobutyrate (CPIB, also known as clofibrate) [6,7], ubiquinone [8,9], diethylhexyl phthalate [10], 1-ethoxysilatrane [11,12]. The affected site in all these cases appears to be HMGCoA reductase in the endoplasmic reticulum from which microsomes are derived.…”

“…We chose for detailed studies the compound, 1-ethoxysilatrane, shown in our laboratory to be a potent hypocholesterolemic agent, whose administration to rats resulted in decrease in concentration in serum [11] and of biogenesis in the liver [12] of cholesterol. Treatment with this compound resulted in decrease in the activity, but not the concentration of the protein, of HMGCoA reductase in microsomes isolated from the liver [12]. We show that the soluble 58 kDa-enzyme, consisting of domains of active site and the linker to the membrane, is inhibited by ethoxysilatrane.…”

Silatranes: a review on their synthesis, structure, reactivity and applications

“…Silatranes were extensively studied after the discovery of specific biological activity of 1-arylsilatrane by Voronkov et al 27 Some reviews are reported on synthetic methods and bioactivity of silatranes [256][257][258][259][260][261][262][263][264] and biochemical roles of Si in animals and birds 265 which suggests the interactions of silatrane structure with biological membranes of feeding minks, sheep, pigs, dairy cattle and chickens. 6.4.1 Pilotropic activity.…”