Metabolism of vitamin K and vitamin K 2,3-epoxide via interaction with a common disulfide.
The effects of thiols and sulfhydryl blocking reagents on the reduction of vitamin K to vitamin K hydroquinone and vitamin K 2,3-epoxide to vitamin K and vitamin K hydroquinone catalyzed by rat hepatic microsomes were investigated to determine the mechanism(s) for these reactions. Both vitamin K and vitamin K 2,3-epoxide reductions were catalyzed more effectively with dithiols than with monothiols as the reductant. The sulfhydryl reagent N-ethylmaleimide (NEM) inhibited vitamin K and vitamin K 2,3-epoxide reduction much more effectively when microsomes were initially treated with dithiothreitol (prereduced). In prereduced microsomes iodoacetamide was approximately half as effective an inhibitor of vitamin K and vitamin K 2,3-epoxide reduction as NEM, but in microsomes not prereduced it was more effective. Iodoacetic acid was ineffective as an inhibitor. Vitamin K or vitamin K 2,3-epoxide added to prereduced microsomes blocked subsequent inhibition by NEM of vitamin K and vitamin K 2,3-epoxide metabolism, respectively. Vitamin K added to prereduced microsomes also blocked inhibition by NEM of vitamin K 2,3-epoxide metabolism, and vitamin K 2,3-epoxide addition blocked inhibition by NEM of vitamin K metabolism. Vitamin K did not diminish the rate of vitamin K 2,3-epoxide metabolism, however, nor did vitamin K 2,3-epoxide diminish the rate of vitamin K metabolism. These data establish that exogenous thiol compounds promote the reduction of at least one protein disulfide which participates in the metabolism of vitamin K and vitamin K 2,3-epoxide. Presumably, the resultant sulfhydryl groups are reoxidized to the disulfide form during the metabolism of either vitamin which protects them from reaction with NEM.
D000818:Animals; D004220:Disulfides / Q000378:metabolism*; D004229:Dithiothreitol / Q000494:pharmacology; D005033:Ethylmaleimide / Q000494:pharmacology; D007460:Iodoacetamide / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014812:Vitamin K / Q000378:metabolism*; D010837:Vitamin K 1 / Q000031:analogs & derivatives* / Q000378:metabolism
D004220:Disulfides; D014812:Vitamin K; C016186:vitamin K1 oxide; D010837:Vitamin K 1; D005033:Ethylmaleimide; D004229:Dithiothreitol; D007460:Iodoacetamide