OXIDATION OF DICLOFENAC TO REACTIVE INTERMEDIATES BY NEUTROPHILS, MYELOPEROXIDASE, AND HYPOCHLOROUS ACID

Diclofenac is associated with a low, but significant, incidence of hep atotoxicity and bone marrow toxicity. It has been suggested that this could be due to a reactive acyl glucuronide. An alternative hypothesis is that an oxidative reactive metabolite could be responsible for suc h reactions and such metabolites formed by the enzymes present in neut rophils could be responsible for bone marrow toxicity. Others had repo rted the formation of 2,2'-dihydroxyazobenzene during the oxidation of diclofenac by myeloperoxidase/hydrogen peroxide. In contrast, in simi lar experiments we did not find evidence for the formation of 2,2'-dih ydroxyazobenzene, but we did find several products, including a reacti ve iminoquinone. The same iminoquinone was formed by the oxidation of 5-hydroxydiclofenac. This iminoquinone was also formed by oxidation of diclofenac by HOCl or by activated neutrophils. It reacted with gluta thione to form a conjugate. 5-Hydroxydiclofenac is also a major hepati c metabolite of diclofenac, and we found that rat hepatic microsomes o xidized 5-hydroxydiclofenac to the iminoquinone which was trapped with glutathione. This reactive metabolite represents another possible cau se of the idiosyncratic reactions associated with the use of diclofena c.