Oxidative metabolism of amsacrine by the neutrophil enzyme myeloperoxidase.
Oxidative metabolism of the anti-cancer drug amsacrine 4'-(9-acridinylamino) methane-sulphan-m-anisidide has been suggested to account for its cytotoxicity. However, enzymes capable of oxidizing it in non-hepatic tissue have yet to be identified. A potential candidate, that may be relevant to the metabolism of amsacrine in blood and its action in myeloid leukaemias and myelosuppression, is the haem enzyme myeloperoxidase. We have found that the purified human enzyme oxidizes amsacrine to its quinone diimine, either directly or through the production of hypochlorous acid. In comparison, the 4-methyl-5-methylcarboxamide derivative of amsacrine, CI-921 9-[[2-methoxy-4[(methylsulphonyl)-amino]phenyl]amino)-N, 5-dimethyl-4-acridine carboxamide, reacted poorly with myeloperoxidase, although it was oxidized by hypochlorous acid. Detailed studies of the mechanism by which myeloperoxidase oxidizes amsacrine revealed that the semiquinone imine free radical is a likely intermediate in this reaction. Oxidation of amsacrine analogues indicated that factors other than their reduction potential determine how readily they are metabolized by myeloperoxidase. Both amsacrine and CI-921 inhibited production of hypochlorous acid by myeloperoxidase. CI-921 acted by trapping the enzyme as the inactive redox intermediate compound II. Amsacrine inhibited by a different mechanism that may involve conversion of myeloperoxidase to compound III, which is also unable to oxidize Cl-. The susceptibility of amsacrine to oxidation by myeloperoxidase indicates that this reaction may contribute to the cytotoxicity of amsacrine toward neutrophils, monocytes and their precursors.
Kettle
A J
AJ
Free Radical Research Unit, Christchurch School of Medicine, New Zealand.
Robertson
I G
IG
Palmer
B D
BD
Anderson
R F
RF
Patel
K B
KB
Winterbourn
C C
CC
D000677:Amsacrine / Q000031:analogs & derivatives / Q000097:blood* / Q000378:metabolism; D006801:Humans; D006997:Hypochlorous Acid / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D009504:Neutrophils / Q000201:enzymology*; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000097:blood* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000677:Amsacrine; D006997:Hypochlorous Acid; D009195:Peroxidase; C042315:asulacrine