Inhibition of human squalene monooxygenase by selenium compounds.
Selenosis in animals is characterized by a variety of neurological abnormalities, but the chemical species of selenium and the molecular targets that mediate this neurotoxicity are unknown. We have previously shown that selenite is a potent inhibitor of squalene monooxygenase, the second enzyme in the committed pathway for cholesterol biosynthesis; inhibition of this enzyme by dimethyltellurium leads to a peripheral demyelinating neuropathy similar to that seen in selenosis. To evaluate the role methylation plays in selenium toxicity, we examined the ability of three methylselenium compounds, methylselenol, dimethylselenide, and trimethylselenonium iodide, to inhibit purified recombinant human squalene monooxygenase. IC(50) values for methylselenol (95 microM) and dimethylselenide (680 microM) were greater than that previously obtained for selenite (37 microM), and inhibition by trimethylselenonium iodide was evident only at concentrations above 3 mM. Inhibition by methylselenol as well as by selenite was slow and irreversible, suggestive of covalent binding to the enzyme, and thiol-containing compounds could prevent and reverse this inhibition, indicating that these compounds were reacting with sulfhydryl groups on the protein. Monothiols such as glutathione and beta-mercaptoethanol provided better protection than did dithiols, suggesting that these selenium compounds bind to only one of the two proposed vicinal cysteines on squalene monooxygenase. Unexpectedly, the inhibition by selenite was significantly enhanced by dithiols, indicating that a more toxic species, possibly selenide, was formed in the presence of these dithiol reductants.
Gupta
Nisha
N
Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA.
Porter
Todd D
TD
D000818:Animals; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D066298:In Vitro Techniques; D000432:Methanol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity*; D009251:NADPH-Ferrihemoprotein Reductase / Q000037:antagonists & inhibitors; D016566:Organoselenium Compounds / Q000378:metabolism / Q000633:toxicity*; D010105:Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018036:Selenium Compounds / Q000378:metabolism / Q000633:toxicity*; D050603:Squalene Monooxygenase; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013997:Time Factors
D004791:Enzyme Inhibitors; D016566:Organoselenium Compounds; D011994:Recombinant Proteins; D018036:Selenium Compounds; D013438:Sulfhydryl Compounds; C019003:methaneselenol; D010105:Oxygenases; D050603:Squalene Monooxygenase; D009251:NADPH-Ferrihemoprotein Reductase; C003717:trimethylselenonium; D000432:Methanol; C013503:dimethylselenide