A high proportion of toxic and carcinogenic effects of chemicals develop through the pathway of lethal synthesis. A part of this pathway is along the inducible
cytochrome P-450-linked
enzyme system. It has previously been suggested that the variations in disease patterns between individuals and between national groups may be due to differences in nutritional intake which in turn act by altering the pathways controlled by
cytochrome P-450. However, patients with
epilepsy, who are taking large amounts of inducing
anticonvulsants, and who are known to have increased
cytochrome P-450-linked
enzyme activity, fail to show clear-cut changes in their patterns of mortality. It is possible that the reactions in the
cytochrome P-450 pathways are not usually rate-limiting steps in toxicity in humans, and that we must look elsewhere, beyond the activation step, for the cause of variability in human responses to toxic materials in the environment. There are in current circulation three major theories of acute cell injury by chemicals. Using isolated liver cells and slices we conclude that none of them offers a reasonable explanation of the events of cell injury and
necrosis in their usual simple form. Lipid peroxidation and
calcium entry into cells can be blocked by
antioxidants and
calcium-free media, without interference with cell injury. Covalent binding of
p-aminophenol to liver is far greater than binding of
paracetamol, but it does not cause cell injury. The reversibility of some cell
injuries implicates the existence of specific metabolic blocks by reactive metabolites rather than any generalized attack by insertion of metabolite groups.