Acetaminophen hepatotoxicity: the first 35 years.
The acetaminophen nomogram including its uses and limitations is discussed as well as the development of the N-acetylcysteine protocol. While it has taken many years to elucidate the genetic variability and true multiplicity of the cytochrome P450 "mixed function oxidase system" many publications early on looked at the enzyme system as a single entity. Numerous articles indicated that barbiturates, anticonvulsants, and others could induce "P450" and add to the toxicity of acetaminophen. It rapidly became apparent that just because "P450" was induced when measured as a whole, not all other substrates would have changed metabolic activity. The role of diet and ethanol induction and inhibition on CYP2E1, the enzyme of greatest interest for acetaminophen is multifaceted. The lack of enhancement of acetaminophen toxicity by phenytoin and in fact, the potential for reduction of toxicity with that agent is a good example of the evolution of our knowledge. Further complicating our understanding is the introduction of misleading terms such as "therapeutic misadventure" and other expressions of molecular intent. A critical understanding of the literature makes it clear that therapeutic doses of acetaminophen either alone or in the presence of inducers do not produce toxicity. While the community of clinical toxicologists is small, it needs to be more aggressive in making sure that physicians from other specialties and non-clinical toxicology colleagues understand the significance and implications of this science.
Rumack
Barry H
BH
University of Colorado School of Medicine and Rocky Mountain Poison and Drug Center, Denver, USA. barry@rumack.com
D000082:Acetaminophen / Q000009:adverse effects* / Q000378:metabolism / Q000627:therapeutic use; D000111:Acetylcysteine / Q000627:therapeutic use; D000410:Alanine Transaminase / Q000097:blood; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects* / Q000378:metabolism / Q000627:therapeutic use; D000927:Anticonvulsants / Q000494:pharmacology; D001219:Aspartate Aminotransferases / Q000097:blood; D001463:Barbiturates / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury; D019392:Cytochrome P-450 CYP2E1 / Q000494:pharmacology; D004359:Drug Therapy, Combination; D004790:Enzyme Induction; D000431:Ethanol / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000187:drug effects*; D008107:Liver Diseases / Q000517:prevention & control; D009747:Nutritional Physiological Phenomena; D010672:Phenytoin / Q000494:pharmacology
D018712:Analgesics, Non-Narcotic; D000927:Anticonvulsants; D001463:Barbiturates; D000082:Acetaminophen; D000431:Ethanol; D010672:Phenytoin; D019392:Cytochrome P-450 CYP2E1; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000111:Acetylcysteine