Evidence for the metabolism of mitozantrone by microsomal glutathione transferases and 3-methylcholanthrene-inducible glucuronosyl transferases.

The metabolism of mitozantrone, a chemotherapeutic agent used in the treatment of breast cancer, has been studied in vitro using rat liver subcellular fractions. This compound would appear to be metabolized by two interesting pathways. One involves conjugation with glucuronic acid, catalyzed most effectively by a 3-methylcholanthrene-inducible glucuronosyl transferase. The other pathway appears to be a glutathione conjugation reaction which requires prior metabolism by cytochrome P-450. The reaction with glutathione appears to be enzymatic as 1-chloro-2,4-dinitrobenzene was a potent inhibitor of this reaction. Liver cytosol did not enhance the microsomal rate of glutathione-conjugate formation, suggesting an important role for the microsomal glutathione transferases in the disposition of this compound. The relationship between these reactions and the mode of action of mitozantrone is discussed.