Miyamoto G, Zahid N, Uetrecht J P
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Chem Res Toxicol. 1997 Apr;10(4):414-9. doi: 10.1021/tx960190k.
Diclofenac is associated with a low, but significant, incidence of hepatotoxicity 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 such reactions and such metabolites formed by the enzymes present in neutrophils could be responsible for bone marrow toxicity. Others had reported the formation of 2,2'-dihydroxyazobenzene during the oxidation of diclofenac by myeloperoxidase/hydrogen peroxide. In contrast, in similar experiments we did not find evidence for the formation of 2,2'-dihydroxyazobenzene, but we did find several products, including a reactive 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 glutathione to form a conjugate. 5-Hydroxydiclofenac is also a major hepatic metabolite of diclofenac, and we found that rat hepatic microsomes oxidized 5-hydroxydiclofenac to the iminoquinone which was trapped with glutathione. This reactive metabolite represents another possible cause of the idiosyncratic reactions associated with the use of diclofenac.
双氯芬酸与低但显著的肝毒性和骨髓毒性发生率相关。有人认为这可能是由于反应性酰基葡萄糖醛酸。另一种假设是氧化反应性代谢物可能是此类反应的原因，而中性粒细胞中存在的酶形成的此类代谢物可能是骨髓毒性的原因。其他人曾报道在髓过氧化物酶/过氧化氢氧化双氯芬酸过程中形成2,2'-二羟基偶氮苯。相比之下，在类似实验中我们没有发现形成2,2'-二羟基偶氮苯的证据，但我们确实发现了几种产物，包括一种反应性亚氨基醌。5-羟基双氯芬酸氧化也形成相同的亚氨基醌。这种亚氨基醌也可由次氯酸或活化的中性粒细胞氧化双氯芬酸形成。它与谷胱甘肽反应形成缀合物。5-羟基双氯芬酸也是双氯芬酸的主要肝代谢物，我们发现大鼠肝微粒体将5-羟基双氯芬酸氧化为被谷胱甘肽捕获 的亚氨基醌。这种反应性代谢物是与使用双氯芬酸相关的特异反应的另一个可能原因。
