Abstract
As one means of determining the extent to which free radical metabolites are involved in the interaction of hepatotoxic drugs with target tissues, we have measured the covalent binding to hepatic lipids of carbon tetrachloride, acetaminophen, 2-furamide, furosemide, dimethylnitrosamine, and bromobenzene. Transesterification of the Folch lipid fraction was required to distinguish radioactive label present but not covalently bound to alkyl residues through radical addition or combination reactions. Although all hepatotoxins were covalently bound to hepatic protein in the range of 1-2 nmoles/mg, thereby confirming tissue alkylation by reactive metabolites under the present experimental conditions, only carbon tetrachloride gave significant covalent binding to the alkyl residues of hepatic lipids (4.34 nmoles/mg). Thus, although these data further support the already well-documented role of a free radical in the reaction of carbon tetrachloride with target tissue molecules, none of the other hepatotoxins gave similar indications. Dimethylnitrosamine did give significant covalent binding to lipids, but the removal of the binding by transesterification indicates that the binding apparently resulted from electrophilic attack on nucleophilic centers present in phospholipids rather than from radical attack on electroneutral alkyl residues of the lipids.
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