Oxidation of mitoxantrone by lactoperoxidase.
The lactoperoxidase (LPO) catalysed oxidation of mitoxantrone, an anthraquinone type anti-cancer drug, was studied spectrophotometrically under turnover and single turnover conditions with a stopped flow apparatus. With Compound I and Compound II, mitoxantrone formed binding complexes that were deactivated with increasing substrate concentration. The productive second-order rate constants for reduction were 3.6 x 10(6) and 2.2 x 10(4) M(-1) s(-1) for Compound I and Compound II, respectively. Under turnover conditions, Compound II was the steady-state intermediate, but with increasing H2O2, Compound II reacted with H2O2 to form the catalytically inactive intermediate Compound III. Nitrite prevented formation of Compound III by reducing Compound II to the native state. It also modulated the pathway of mitoxantrone oxidation by increasing the level of oxidised metabolites such as MH2(2+) and the novel metabolite MH. The biological implication of drug activation by LPO with nitrite is discussed.
Brück
Thomas B
TB
School of Chemical and Life Sciences, University of Greenwich, Central Avenue, Chatham Maritime, Kent ME4 4TB, UK.
Harvey
Patricia J
PJ
D002384:Catalysis; D006861:Hydrogen Peroxide / Q000737:chemistry; D007074:Immunoglobulin G / Q000737:chemistry; D007700:Kinetics; D007784:Lactoperoxidase / Q000737:chemistry*; D008558:Melphalan / Q000737:chemistry; D008942:Mitoxantrone / Q000737:chemistry*; D008956:Models, Chemical; D015394:Molecular Structure; D009573:Nitrites / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D009195:Peroxidase / Q000737:chemistry*; D013057:Spectrum Analysis / Q000379:methods
D007074:Immunoglobulin G; D009573:Nitrites; C051713:antineoplastic agent K 18; D006861:Hydrogen Peroxide; D008942:Mitoxantrone; D007784:Lactoperoxidase; D009195:Peroxidase; D008558:Melphalan