Xenobiotics, drug metabolism, and liver injury.

The covalent binding hypothesis has been and remains a dominant organizing principle in biochemical pathology. Cellular injury mediated by the interaction of chemically reactive metabolites with macromolecules has been invoked to account for the liver cell death produced by a wide variety of xenobiotic chemicals and drugs. The evidence to support such a role for covalent binding is largely circumstantial and is based on the persistent correlation between the extent of binding and the severity of the accompanying liver necrosis. The more recent studies of the toxicity of haloalkanes (e.g., carbon tetrachloride), aryl halides (e.g., bromobenzene), and compounds capable of redox cycling with dioxygen (e.g., acetaminophen) have suggested alternative mechanisms for coupling mixed function oxidation to lethal cell injury. In this review, I have sketched the outlines of an emerging scheme that places emphasis on variations in the normal mixed function oxidation cycle that derive from the chemical properties of the hepatotoxin in question. I discussed three different causes--biochemical lesions, if you will--of variations with three classic hepatotoxins, carbon tetrachloride, acetaminophen, and bromobenzene. The nature of the variation and how it presumably leads to liver cell injury was reviewed.