Mechanism of metabolic activation of ronidazole, a 5-nitroimidazole.

bromophenol is formed from bromobenzene-3,4-oxide nonenzymically, the decrease in p-bromophenol formation may be used as an indirect measure of the decrease in the extracellular concentration of bromobenzene-3,4-oxide in the presence of the transferase. From these data, we found that only negligible amounts of the epoxide re-entered the cells; that is, kZ1 was negligible and that about 59% of the epoxide escaped the cells. This implies, however, that virtually all of the 3,4-dihydrobromobenzene-3,4-diol was formed extracellularly, because the formation of this metabolite was decreased by the addition of the GSH transferase B. Indeed, a plot of the rate of formation of the 3,4-di hydrobromobenzene-3,4-diol versus the rate of formation ofpbromophenol is consistent with the view that both are formed from the same kinetic compartment. From theoretical considerations, however, it is unlikely that the 3,4-dihydrobromobenzene-3,4-diol is formed nonenzymically. Instead, in the absence of enzymes, the arene oxide should decompose almost entirely to p-bromophenol. This would suggest, therefore, either that the theory is wrong or that the hepatocyte preparation became contaminated with microsomal membranes from cells destroyed during isolation. From these studies it is clear that the arene oxides of bromobenzene are at least sufficiently long-lived within rat hepatocytes to belong to the category of intermediate-lived metabolites. Thus these metabolites may leave the cells in which they are formed and probably enter neighbouring cells. They also probably enter blood, where they may react with various components, including erythrocytes, and are swept downstream by the blood where they enter other hepatocytes or perhaps cells of other organs. Indeed, we have recently obtained indirect evidence that bromobenzene-3,4-oxide is present in systemic blood of rats receiving bromobenzene, which suggests the possibility that bromobenzene-3,4-oxide formed in liver may contribute to the toxicity of bromobenzene in extrahepatic organs (Lau et al., 1983).