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 11, 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 11, respectively. Under turnover conditions, Compound 11 was the steady-state intermediate, but with increasing H2O2, Compound 11 reacted with H2O2 to form the catalytically inactive intermediate Compound III. Nitrite prevented formation of Compound III by reducing Compound 11 to the native state. It also modulated the pathway of mitoxantrone oxidation by increasing the level of oxidised metabolites such as MH22+ and the novel metabolite MH. The biological implication of drug activation by LPO with nitrite is discussed. (C) 2003 Elsevier B.V All rights reserved.