Free radical intermediates under hypoxic conditions in the metabolism of halogenated carcinogens

Many halogenated hydrocarbons are known to have carcinogenic potency, nevertheless, humans may be exposed to such xenobiotics for prolonged periods during industrial occupations. In this study, eight aliphatic haloalkanes, all suspected carcinogens, have been studied with respect to their metabolic activation to free radical intermediates, that may exert toxic effects when produced in vivo. The eight haloalkanes studied here are: carbon tetrachloride, chloroform, 1,2-dibromoethane, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane and 1,1,2,2-tetrachloroethane. Using isolated rat hepatocytes as a model system, and electron spin resonance spectroscopy coupled to the spin trapping technique as a detection technique, it has been possible to demonstrate the formation of free radical derivatives, both under normoxic as well as under hypoxic conditions from carbon tetrachloride, chloroform, 1,1,1-tetrachloroethane and 1,1,2,2-tetrachloroethane. In contrast, free radical production was only detectable under hypoxic conditions when 1,2-dibromoethane, 1,1-dichloroethane, 1,2-dichloroethane and 1,1,2-trichloroethane were added to the hepatocyte suspensions. It is known that some xenobiotics that usually undergo oxidative pathways of metabolism can be metabolized differently when the oxygen concentration is substantially diminished. Evidence have been obtained suggesting that such different types of metabolism may be of relevance in vivo. Possible relationships between free radical production, metabolic activation, covalent binding and carcinogenic potency are discussed.