Abstract
Menadione (MD, vitamin K3), the highly toxic substance, is formed as a metabolic intermediate in the process of producing vitamin K2 from vitamin K1in vivo. Here, we investigated whether there is a pathway by which MD is reduced and then sulfated by sulfotransferase (SULT) as a reason why MD has not shown any toxicity despite its formation in vivo. Human SULT isoforms involved in the sulfation of the reduced form of MD (MD-OH) were studied. In addition, glucuronidating and sulfating activities in human liver S9 toward MD-OH were investigated to evaluate the contribution of UDP-glucuronosyltransferase (UGT) and SULT in the conjugation reaction following two-electron reduction of MD by NAD(P)H:quinone oxidoreductase 1 (NQO1). In the human liver cytosol, MD-4-O-sulfate was predominantly produced. SULTs 1A1, 1A3, 1B1 and 1E1 showed sulfating activity toward MD-OH. MD-4-O-sulfate was predominantly produced in all isoforms showed MD-OH sulfating activity, but only SULTs 1A3 and 1E1 produced MD-1-O-sulfate. SULT1A1, which is expressed at a high level in the liver, was revealed to be the most important factor in the sulfation of MD-OH in the liver. The contribution of UGT and SULT in the conjugation of MD-OH was examined using human liver S9. The results suggested that at low concentrations of MD, sulfation proceeded predominantly, and at high concentrations, glucuronidation proceeded predominantly.
