for leukemogenesis in the management of myeloproliferative disorders Nitric oxide generation from hydroxyurea: significance and implications

Summary and concluding remarks It is concluded that HU is not directly mutagenic. In moststudies where it has been demonstrated to damage DNAdirectlythis can be attributed to the production of nitrogen dioxideduring the autoxidation of nitric oxide 31-33 ; these reactions arenot expected to be of importance in vivo. 28 HU could, however,induce DNA damage if the nitric oxide it yields upon oxidationhas the opportunity to combine with superoxide, which leads tothe production of nitrogen dioxide and other powerful oxidants.Superoxide is most likely to be available to combine with nitricoxide at sites of inflammation, where MPO might well play animportant role in the oxidation of HU. However, under theseconditions the same oxidants would also be generated throughthe concerted actions of iNOS and NAD(P)H oxidase, 45 so thesignifance of additional nitric oxide generation from HU needsto be investigated. Additional nitric oxide might even beprotective through its binding to the heme sites of MPO andiNOS, thereby blocking their generation of reactive species.PGHS may play a more important role than MPO in the releaseof nitric oxide from HU in bone marrow, where there may be lessopportunity for the conversion of nitric oxide to harmful oxidants.Indeed, an investigation into the myelotoxicity of benzene identi-fied a role for PGHS, rather than MPO, in the oxidation of itshydroquinonemetaboliteto