The initial key step in APAP-induced hepatotoxicity is metabolism to the reactive metabolite NAPQI.
If kava depletes GSH, this would leave less GSH to detoxify NAPQI as it is formed and this would result in potentiation of the toxic effects of APAP.
APAP, via NAPQI, has been shown to alter mitochondrial function, ultimately leading to a critical chain of events that leads to cell death.
2] Nonstandard abbreviations: NAPQI
, N-acetyl-p-benzoquinoneimine; NAC, N-acetylcysteine.
The percentage of APAP converted to NAPQI by CYP2E1 is increased when APAP conjugation pathways become saturated.
14) Human fetal microsomes and isolated fetal hepatocytes have been shown to be able to metabolize acetaminophen into NAPQI, although at a slower rate than adults.
Acetaminophen overdoses now are treated with a compound that increases the body's production of glutathione, a naturally occurring molecule that neutralizes NAPQI
Our data indicated AA could alleviate oxidation stimulation, which related with oxidative stress might cause induction of HIF-1[alpha] Thus we should notice the same tendency in other antioxidases alternation, oxidative stress might be a potential role in APAP-mediated induction of HIF-1[alpha] The finding that AA and silymarin blocked HIF-1[alpha] induction would show that HIF-1[alpha] induction occurred because of the toxic metabolite NAPQI
A well-known antidote for acetaminophen-induced NAPQI poisoning (secondary to acetaminophen poisoning) is administration of NAC.
glucuronidation) and also reduces glutathione stores, leading to accumulation of NAPQI.
3] Nonstandard abbreviations: NSAID, nonsteroidal antiinflammatory drug; TDM, therapeutic drug monitoring; CYP, cytochrome; CSF, cerebrospinal fluid; GC, gas chromatography; GC-MS, gas chromatography mass spectrometry; NAPQI
, N-acetyl-p-benzoquinonimine; and CNS, central nervous system.
It is well known that a large dose of acetaminophen causes hepatic GSH depletion because NAPQI
reacts rapidly with glutathione (Nelson, 1990; Oz et al.