Liver microsome and flavin-containing monooxygenase catalyzed oxidation of organic selenium compounds.
Eight commercially available selenides, a selenol, and selenourea were examined for substrate activity with purified pig liver flavin-containing monooxygenase (FMO). While none of the aromatic heterocyclic selenides tested showed detectable activity, all dialkyl- and alkylaryl-selenides free from ionic groups stimulated NADPH- and FMO-dependent oxygen uptake. With limiting substrate the molar ratio of oxygen reduced to selenide added was 1:1. Analysis of products from N-[2-(methylseleno)ethyl]benzamide demonstrated that the selenide was quantitatively oxidized to selenoxide. Further oxidation of either the FMO-generated or synthetic selenoxides was not detected. The dialkyl- and alkylaryl-selenoxides are potent thiol oxidants and reaction rates for the oxidation of thiols by methylphenylselenoxide and N-[2-(methylseleninyl)ethyl]benzamide followed second order kinetics with rate constants from 3-4 x 10(3) M-1 s-1 at pH 7.4, 37 degrees C. The rapid oxidation of thiols by these selenoxides demonstrates that the oxidation of selenides to selenoxides catalyzed by crude tissue preparations can be measured by following selenide-dependent oxidation of thiocholine by the procedure described earlier for the oxidation of thiourea (WXA Guo and D. M. Ziegler, 1991, Anal. Biochem. 198, 143-148). Activity measurements by this procedure indicated that the oxidation of dialkyl selenides by rat, guinea pig, or pig liver microsomes was catalyzed primarily by a monooxygenase with the properties of FMO. However, from 20 to 40% of the microsome-catalyzed oxidation of selenides bearing aryl substituents was sensitive to N-benzylimidazole, suggesting that P450-dependent monooxygenases also contribute, at least in part, to the oxidation of these xenobiotics.
Chen
G P
GP
Department of Chemistry and Biochemistry, University of Texas at Austin 78712.
Ziegler
D M
DM
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D004789:Enzyme Activation; D005415:Flavins; D005978:Glutathione / Q000378:metabolism; D006168:Guinea Pigs; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D008954:Models, Biological; D016566:Organoselenium Compounds / Q000378:metabolism*; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013552:Swine
D065607:Cytochrome P-450 Enzyme Inhibitors; D005415:Flavins; D016566:Organoselenium Compounds; D013438:Sulfhydryl Compounds; D010105:Oxygenases; D005978:Glutathione