RELATIONSHIP OF FREE RADICALS TO HALOCARBON-INDUCED TOXICITY IN THE LIVER

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CCl4 has been shown previously to be metabolized to the trichloromethyl radical (.CCl3) and to a novel oxygen-containing carbon dioxide anion radical (.CO2) in the perfused rat liver. The CO2 radical adduct also was observed in urine following the intragastric administration of CCl4 or CBrCl3 and spin trap. The rate of formation of CO2 radical adduct was decreased 2-3 fold following inhibition of cytochrome P-450-dependent mono-oxygenases by metyrapone (0.5 mM) and was increased about two-fold by induction of cytochrome P-450 by phenobarbital pretreatment. Toxicity of halocarbons in the perfused liver was assessed by measuring the release of lactate dehydrogenase (LDH) into the effluent perfusate in livers from phenobarbital-treated rats under conditions identical to those employed to detect radical adducts. Metabolism of halocarbons to the CO2 radical adduct was 6-8 fold faster during perfusion with nitrogen-saturated rather than with oxygen-saturated perfusate. Concomitantly, liver damage detected from LDH release occurred much sooner during halocarbon infusion in the presence of nitrogen-saturated perfusate. A good correlation (r= -0.8) between the rate of formation of PBN/CO2 and the time to onset of LDH release following halocarbon infusion was observed. Therefore, it is concluded that PBN/CO2 is a useful marker for the free radical intermediates that are casually related to halocarbon-induced hepatotoxicity. Recently, the CCl3 and CO 2 radical adducts also have been detected in the bile from anesthetized rats. Hypoxia or pretreatment with phenobarbital has been reported to enhance the hepatotoxicity of CCl4, in vivo; these treatments also produced an increase in the biliary concentration of the PBN/CCl3 radical adduct and in the CCl3-derived PBN/CO2 radical adduct as well. ESR analysis of bile from animals treated with free radical traps and other xenobiotics, such as ethanol, may prove useful in monitoring hepatic free radical-adduct formation in vivo.