Tellurium Blocks Cholesterol Synthesis by Inhibiting Squalene Metabolism: Preferential Vulnerability to This Metabolic Block Leads to Peripheral Nervous System Demyelination

Abstract

Inclusion of 1.1% elemental tellurium in the diet of postweanling rats produces a peripheral neuropathy due to a highly synchronous primary demyelination of sciatic nerve; this demyelination is followed closely by remyelination. Sciatic nerves from animals fed tellurium for various times were removed and incubated ex vivo for 1 h with [14C]acetate, and radioactivity incorporated into individual lipid classes was determined. In nerves from rats exposed to tellurium, there was a profound and selective block in the conversion of radioactive acetate to cholesterol. Another radioactive precursor, [3H]water, gave similar results. We suggest that tellurium feeding inhibits squalene epoxidase activity and that the consequent lack of cholesterol destabilizes myelin, thereby causing destruction of the larger internodes. Ex vivo incubation experiments were also carried out with liver slices. As with nerve, tellurium feeding caused accumulation in squalene of label from radioactive acetate, whereas labeling of cholesterol was greatly inhibited. Unexpectedly, however, incorporation of label from [3H]water into both squalene and cholesterol was increased. Relevant is the demonstration that liver was the primary site of bulk accumulation of squalene, which accounted for 10% of liver dry weight at 5 days. Thus, accumulation of squalene (and other mechanisms, possibly including up-regulation of cholesterol biosynthetic pathways) drives squalene epoxidase activity at normal levels in liver even in the presence of inhibitors of this enzyme. This is reflected by continuing incorporation of [3H]water into cholesterol; incorporation of this precursor takes place at many of the postsqualene biosynthetic steps for sterol formation. [14C]Acetate entering the sterol pathway before squalene in liver is greatly diluted in specific activity when it reaches the large squalene pool, and thus increased squalene epoxidase activity does not transfer significant 14C label to sterols. In contrast to the situation with liver, synthesis of sterols is markedly depressed in sciatic nerve, and squalene does not accumulate to high levels.

A glimpse on biological activities of tellurium compounds

“…From the blockage of cholesterol synthesis, a transient demyelination of peripheral nerves occur (Wagner-Recio et al 1991, Wagner et al 1995. The same effect has been observed with selenite and other methylselenium compounds (Gupta and Porter 2002).…”

Relationship of iron to oligondendrocytes and myelination

“…Iron-requiring enzymes leading to lipid synthesis (fatty acid desaturase) and degradation (lipid dehydrogenases) are enriched in oligodendrocytes (Bourre et al, 1984;Cammer, 1984;Tansey and Cammer, 1988). The peripheral demyelination associated with tellurium toxicity is thought to result from blockage of the ironrequiring squalene oxidase step in cholesterol biosynthesis (Wagner-Recio et al, 1991).…”

Squalene monooxygenase – a target for hypercholesterolemic therapy

“…There are several studies demonstrating that they interact with many other proteins (Hanther , 1968 ;Bjornstedt et al , 1996 ;Barbosa et al , 1998 ;Park et al , 2000 ). Moreover, allyl compounds cross through the blood-brain barrier and inhibit SE in Schwann cells blocking myelin formation, leading as a consequence to peripheral segmental demyelination and paralysis (Wagner -Recio et al, 1991 ;Ammar and Couri , 1992 ;Stowe et al , 1992 ). It excludes them as candidates for cures in modern therapy.…”