Effect of Mixed-Function Oxidase Modifiers on Metabolism and Toxicity of the Oncogen Dioxane1

With both nonradioactive and "*C-labeled dioxane, the effect of typical inducers and inhibitors of hepatic mixedfunction oxidases on the excretion of p-dioxane-2-one, the major urinary metabolite of dioxane, was studied. Pretreatment of rats with the inducers phénobarbital (PB), polychlorinated biphenyls (PCB), and, to a much lesser extent, 3-methylcholanthrene (MC) increased the metab olite excretion and shortened the time of onset of peak excretion of the metabolite. On the other hand, an inhibi tor or represser of mixed-function oxidases such as 2,4dichloro-6-phenylphenoxyethylamine and cobaltous chlo ride decreased the metabolite excretion. The results sug gest the involvement of mixed-function oxidases in the in vivo metabolism of dioxane. The relationship between the metabolism and the acute toxicity of dioxane was ex plored. p-Dioxane-2-one [50% lethal dose = 0.79 ±0.15 g/kg] was considerably more toxic than was dioxane, suggesting that increased metabolism of the latter may bring about increased toxicity. The 50% lethal dose of dioxane in control, PCB-, MC-, and PB-pretreated rats was 5.3 ±0.1, 4.4 ±0.1, 5.2 ±0.1, and 5.4 ±0.2 g/kg, respectively. Thus, there was an apparent correlation between the metabolism and toxicity of dioxane in PCBor MC-pretreated rats, whereas PB had no effect on the toxicity of the solvent. The apparent lack of PB effect may be explained by the possibility that p-dioxane-2-one may be further metabolized to exert its toxic effect. Indeed, pretreatment of rats with PCB or MC further increased the toxicity of p-dioxane-2-one, whereas PB appeared to have an opposite effect. It is proposed that the generation of the toxic substance from dioxane may involve a multistep mechanism with p-dioxane-2-one as an intermediate.