Inhibition of human squalene monooxygenase by tellurium compounds: evidence of interaction with vicinal sulfhydryls.
Squalene monooxygenase is a flavin adenine dinucleotide-containing, microsomal enzyme that catalyzes the second step in the committed pathway for cholesterol biosynthesis. Feeding weanling rats a diet containing 1% elemental tellurium causes a transient, peripheral demyelination due to the disruption of cholesterol synthesis in Schwann cells secondary to inhibition of squalene monooxygenase. The tellurium species responsible for the inhibition is unknown, as is the mechanism of inhibition. To study the potential mechanisms of tellurium toxicity in humans, three likely in vivo metabolites of tellurium (tellurite, dimethyltellurium dichloride, and dimethyltelluride) were tested as inhibitors of purified human squalene monooxygenase. All three inhibitors reacted with the enzyme slowly and the resulting interaction was not freely reversible. The 50% inhibitory concentration for the methyltellurium compounds (approximately 100 nM) after a 30-min preincubation was 100-fold lower than that of tellurite, indicating a role for hydrophobicity in the enzyme-inhibitor interaction. The ability of glutathione and 2,3-dimercaptopropanol to prevent and reverse the inhibition indicated that the tellurium compounds were reacting with sulfhydryls on squalene monooxygenase, and the ability of phenylarsine oxide, which reacts specifically with vicinal sulfhydryls, to inhibit the enzyme indicated that these sulfhydryls are located proximal to one another on the enzyme. These results suggest that the unusual sensitivity of squalene monooxygenase to tellurium compounds is due to the binding of these compounds to vicinal cysteines, and that methylation of tellurium in vivo may enhance the toxicity of tellurium for this enzyme.
Laden
B P
BP
Graduate Center for Toxicology, University of Kentucky, Lexington 40536, USA.
Porter
T D
TD
D001152:Arsenicals / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D010105:Oxygenases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D050603:Squalene Monooxygenase; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D013691:Tellurium / Q000378:metabolism / Q000494:pharmacology*
D001152:Arsenicals; D004791:Enzyme Inhibitors; D013438:Sulfhydryl Compounds; C029341:oxophenylarsine; D010105:Oxygenases; D050603:Squalene Monooxygenase; D013691:Tellurium