Probable free radical effects on rat liver nuclei during early hepatocarcinogenesis with a choline-devoid low methionine diet

Fischer-344 rats fed a choline-devoid diet show lipid peroxidation in the liver nuclei, beginning at 1 day, reaching a peak at 3 days, and subsequently declining by 35 days. Lipid peroxidation in the mitochondria was seen first at 3 days, increased to a maximum at 28 days, and decreased after 35 days to undetectable values at 49 days. Lipid peroxidation was found in both nuclear and mitochondrial fractions both before and after stripping of their outer membranes. No microsomal lipid peroxidation could be detected at any time up to 63 days. The animals fed the same diet supplemented with choline showed no lipid peroxidation in any liver fraction. Animals given CCl4 showed the expected lipid peroxidation in the microsomes but not in the nuclear fraction. The administration of the free radical trapping agent, N-tert-butyl-alpha-phenylnitrone, prevented completely or almost so, microsomal lipid peroxidation induced by CCl4 and nuclear lipid peroxidation in the animals fed the choline-devoid, low methionine diet. The genesis of free radicals in the livers of rats fed a choline-devoid diet is considered as a likely hypothesis for the observed lipid peroxidation. The lipid peroxidation in turn is considered to be closely related to the induction of liver cell death and to the production of alterations in DNA. The DNA alterations coupled with regenerative liver cell proliferation suggest an attractive hypothesis for the initiation of hepatocarcinogenesis in rats fed a choline-devoid diet.