PMID- 14625346
OWN - NLM
STAT- MEDLINE
DCOM- 20040715
LR  - 20220330
IS  - 0090-9556 (Print)
IS  - 0090-9556 (Linking)
VI  - 31
IP  - 12
DP  - 2003 Dec
TI  - Acetaminophen-induced hepatotoxicity.
PG  - 1499-506
AB  - The analgesic acetaminophen causes a potentially fatal, hepatic centrilobular 
      necrosis when taken in overdose. The initial phases of toxicity were described in 
      Dr. Gillette's laboratory in the 1970s. These findings indicated that 
      acetaminophen was metabolically activated by cytochrome P450 enzymes to a 
      reactive metabolite that depleted glutathione (GSH) and covalently bound to 
      protein. It was shown that repletion of GSH prevented the toxicity. This finding 
      led to the development of the currently used antidote N-acetylcysteine. The 
      reactive metabolite was subsequently identified to be N-acetyl-p-benzoquinone 
      imine (NAPQI). Although covalent binding has been shown to be an excellent 
      correlate of toxicity, a number of other events have been shown to occur and are 
      likely important in the initiation and repair of toxicity. Recent data have shown 
      that nitrated tyrosine residues as well as acetaminophen adducts occur in the 
      necrotic cells following toxic doses of acetaminophen. Nitrotyrosine was 
      postulated to be mediated by peroxynitrite, a reactive nitrogen species formed by 
      the very rapid reaction of superoxide and nitric oxide (NO). Peroxynitrite is 
      normally detoxified by GSH, which is depleted in acetaminophen toxicity. NO 
      synthesis (serum nitrate plus nitrite) was dramatically increased following 
      acetaminophen. In inducible nitric oxide synthase (iNOS) knockout mice, 
      acetaminophen did not increase NO synthesis or tyrosine nitration; however, 
      histological evidence indicated no difference in toxicity. Acetaminophen did not 
      cause hepatic lipid peroxidation in wild-type mice but did cause lipid 
      peroxidation in iNOS knockout mice. These data suggest that NO may play a role in 
      controlling lipid peroxidation and that reactive nitrogen/oxygen species may be 
      important in toxicity. The source of the superoxide has not been identified, but 
      our recent finding that NADPH oxidase knockout mice were equally sensitive to 
      acetaminophen and had equal nitration of tyrosine suggests that the superoxide is 
      not from the activation of Kupffer cells. It was postulated that NAPQI-mediated 
      mitochondrial injury may be the source of the superoxide. In addition, the 
      significance of cytokines and chemokines in the development of toxicity and 
      repair processes has been demonstrated by several recent studies. IL-1beta is 
      increased early in acetaminophen toxicity and may be important in iNOS induction. 
      Other cytokines, such as IL-10, macrophage inhibitory protein-2 (MIP-2), and 
      monocyte chemoattractant protein-1 (MCP-1), appear to be involved in hepatocyte 
      repair and the regulation of proinflammatory cytokines.
FAU - James, Laura P
AU  - James LP
AD  - Department of Pediatrics, University of Arkansas for Medical Sciences, Little 
      Rock, Arkansas, USA. jameslaurap@uams.edu
FAU - Mayeux, Philip R
AU  - Mayeux PR
FAU - Hinson, Jack A
AU  - Hinson JA
LA  - eng
GR  - DK 02971/DK/NIDDK NIH HHS/United States
GR  - GM 58884/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PT  - Review
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (Analgesics, Non-Narcotic)
RN  - 0 (Antidotes)
RN  - 0 (Cytokines)
RN  - 3604-79-3 (3-nitrotyrosine)
RN  - 362O9ITL9D (Acetaminophen)
RN  - 42HK56048U (Tyrosine)
RN  - WYQ7N0BPYC (Acetylcysteine)
SB  - IM
MH  - Acetaminophen/*adverse effects/metabolism
MH  - Acetylcysteine/therapeutic use
MH  - Analgesics, Non-Narcotic/*adverse effects/metabolism
MH  - Antidotes/therapeutic use
MH  - *Chemical and Drug Induced Liver Injury
MH  - Cytokines/metabolism
MH  - Humans
MH  - Kupffer Cells/metabolism
MH  - Liver Diseases/drug therapy/metabolism
MH  - Mitochondria, Liver/metabolism
MH  - Oxidative Stress/drug effects
MH  - Tyrosine/*analogs & derivatives/metabolism
RF  - 80
EDAT- 2003/11/20 05:00
MHDA- 2004/07/16 05:00
CRDT- 2003/11/20 05:00
PHST- 2003/11/20 05:00 [pubmed]
PHST- 2004/07/16 05:00 [medline]
PHST- 2003/11/20 05:00 [entrez]
AID - 31/12/1499 [pii]
AID - 10.1124/dmd.31.12.1499 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2003 Dec;31(12):1499-506. doi: 10.1124/dmd.31.12.1499.