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

Seamen's Memorial Research Laboratory, U. S. Public Health Service Hospital, New Orleans, Louisiana 70118, and Department of Medicine, Tulane University Medical Center, New Orleans, Louisiana

With both nonradioactive and ¹⁴C-labeled dioxane, the effect of typical inducers and inhibitors of hepatic mixed-function oxidases on the excretion of p-dioxane-2-one, the major urinary metabolite of dioxane, was studied. Pretreatment of rats with the inducers phenobarbital (PB), polychlorinated biphenyls (PCB), and, to a much lesser extent, 3-methylcholanthrene (MC) increased the metabolite excretion and shortened the time of onset of peak excretion of the metabolite. On the other hand, an inhibitor or repressor of mixed-function oxidases such as 2,4-dichloro-6-phenylphenoxyethylamine and cobaltous chloride decreased the metabolite excretion. The results suggest 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 explored. 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 PCB- or 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.

¹ Supported by Research Grant CA-15111 from the National Cancer Institute and Grant 922M from The Council for Tobacco Research (U. S. A.). Presented in part at the 68th Annual Meeting of the American Association for Cancer Research, Inc., Denver, 1977 (33).

Received 11/15/77. Accepted 3/ 9/78.