The influence of nutrition and inducers on mechanisms of toxicity in humans and animals.
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.
D000082:Acetaminophen / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D002118:Calcium / Q000494:pharmacology; D002273:Carcinogens; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004827:Epilepsy / Q000201:enzymology / Q000401:mortality; D005503:Food Additives / Q000009:adverse effects; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009747:Nutritional Physiological Phenomena; D010634:Phenobarbital / Q000009:adverse effects / Q000627:therapeutic use; D051381:Rats; D014116:Toxicology; D014810:Vitamin E / Q000494:pharmacology
D000927:Anticonvulsants; D002273:Carcinogens; D005503:Food Additives; D014810:Vitamin E; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System; D002118:Calcium; D010634:Phenobarbital