NAPQI

同

N-acetyl-β-benzoquinoneimine

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/08/14 07:15:45」(JST)

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NAPQI

Identifiers
IUPAC name N-(4-Oxo-1-cyclohexa-2,5-dienylidene)acetamide
Synonyms	N-Acetyl-p-benzoquinone imine; N-Acetylimidoquinone
CAS Number	50700-49-7 N
PubChem CID	39763
IUPHAR/BPS	6299
ChemSpider	36356 Y
UNII	G6S9BN13TI
ChEBI	CHEBI:29132 Y
ChEMBL	CHEMBL33232 Y
ECHA InfoCard	100.168.312
Chemical and physical data
Formula	C8H7NO2
Molar mass	149.147 g/mol
3D model (JSmol)	Interactive image
SMILES O=C\1/C=C\C(=N/C(=O)C)/C=C/1
InChI InChI=1S/C8H7NO2/c1-6(10)9-7-2-4-8(11)5-3-7/h2-5H,1H3 Y Key:URNSECGXFRDEDC-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

NAPQI (N-acetyl-p-benzoquinone imine) is a toxic byproduct produced during the xenobiotic metabolism of the analgesic paracetamol (acetaminophen). It is normally produced only in small amounts, and then almost immediately detoxified in the liver.

However, under some conditions in which NAPQI is not effectively detoxified (usually in case of paracetamol overdose), it causes severe damage to the liver. This becomes apparent 3–4 days after ingestion and may result in death from fulminant liver failure several days after the overdose.

Metabolism

Acetaminophen (paracetamol) metabolism (click to enlarge). Pathways shown in blue and purple lead to non-toxic metabolites; the pathway in red leads to NAPQI, which is toxic if not conjugated to glutathione.

In adults, the primary metabolic pathway for paracetamol is glucuronidation. This yields a relatively non-toxic metabolite, which is excreted into bile and passed out of the body. A small amount of the drug is metabolized via the cytochrome P-450 pathway (to be specific, CYP3A4 and CYP2E1) into NAPQI, which is extremely toxic to liver tissue, as well as being a strong biochemical oxidizer. In an average adult, only a small amount (approximately 10% of a therapeutic paracetamol dose) of NAPQI is produced, which is inactivated by conjugation with glutathione. The amount of NAPQI produced differs in certain populations.

The minimum dosage at which paracetamol causes toxicity usually is 7.5 to 10g in the average person. The lethal dose is usually between 10 g and 15 g. Concurrent alcohol intake lowers these thresholds significantly. Chronic alcoholics may be more susceptible to adverse effects due to reduced glutathione levels. Other populations may experience effects at lower or higher dosages depending on differences in P-450 enzyme activity and other factors which affect the amount of NAPQI produced. In general, however, the primary concern is accidental or intentional paracetamol overdose. Since the drug is available over the counter in most jurisdictions, it is a common choice for suicide attempts.

When a toxic dose of paracetamol is ingested, the normal glucuronide pathway is saturated and large amounts of NAPQI are produced. Liver reserves of glutathione are depleted by conjugation with this excess NAPQI. The mechanism by which toxicity results is complex, but is believed to involve reaction between unconjugated NAPQI and critical proteins as well as increased susceptibility to oxidative stress caused by the depletion of glutathione.

Poisoning

The prognosis is good for paracetamol overdoses if treatment is initiated up to 8 hours after the drug has been taken. Most hospitals stock the antidote (acetylcysteine), which replenishes the liver's supply of glutathione, allowing the NAPQI to be metabolized safely. Without early administration of the antidote, fulminant liver failure follows, often in combination with kidney failure, and death generally occurs within several days.

Antidote

The preferred antidote for NAPQI poisoning (usually secondary to paracetamol poisoning) is N-acetylcysteine. It can be given in large amounts without side-effects. The amino acid methionine can also be used effectively as an antidote for NAPQI toxicity. The antidote should be held off to get blood paracetamol levels if the levels can be obtained with in 8 hours post-ingestion. There is little indication of giving the anti-dote before 8 hours.

See also

• paracetamol poisoning
• paracetamol
• glucuronidation
• cytochrome P450 oxidase
• glutathione
• acetylcysteine
• methionine
• liver failure
• Metabolism

External links

• Alsalim W, Fadel M (July 2003). "Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Oral methionine compared with intravenous N-acetyl cysteine for paracetamol overdose". Emerg Med J. 20 (4): 366–7. PMC 1726135 . PMID 12835357. doi:10.1136/emj.20.4.366. 
• van de Straat R, de Vries J, Debets AJ, Vermeulen NP (July 1987). "The mechanism of prevention of paracetamol-induced hepatotoxicity by 3,5-dialkyl substitution. The roles of glutathione depletion and oxidative stress". Biochem. Pharmacol. 36 (13): 2065–70. PMID 3606627. doi:10.1016/0006-2952(87)90132-8. 
• Cytochrome P-450 Inducers, Inhibitors, and Substrates

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. 成人におけるアセトアミノフェン（パラセタモール）中毒：病態生理、症状、および診断 acetaminophen paracetamol poisoning in adults pathophysiology presentation and diagnosis
• 2. 小児および思春期の患者におけるアセトアミノフェン（パラセタモール）中毒のマネージメント management of acetaminophen paracetamol poisoning in children and adolescents
• 3. 小児および思春期の患者における アセトアミノフェン（パラセタモール）中毒の臨床症状および診断 clinical manifestations and diagnosis of acetaminophen paracetamol poisoning in children and adolescents
• 4. 進行慢性肝疾患または肝硬変患者における疼痛管理 management of pain in patients with advanced chronic liver disease or cirrhosis
• 5. 肝生検標本の解釈 interpretation of liver biopsy specimens

English Journal

• A reliable method of liquid chromatography for the quantification of acetaminophen and identification of its toxic metabolite N-acetyl-p-benzoquinoneimine for application in pediatric studies.

• Flores-Perez C, Chavez-Pacheco JL, Ramirez-Mendiola B, Alemon-Medina R, Garcia-Alvarez R, Juarez-Olguin H, Flores-Perez J.SourceLaboratorio de Farmacologia, Instituto Nacional de Pediatria, Mexico.
• Biomedical chromatography : BMC.Biomed Chromatogr.2011 Jul;25(7):760-6. doi: 10.1002/bmc.1511. Epub 2010 Sep 27.
• The aim of the present study was to develop a simple, selective and reliable method to quantify acetaminophen and its toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI) for pediatric studies using 100?μL plasma samples, by reverse-phase HPLC and UV detection. The assay was performed using a C(
• PMID 20878659

• Aldo-keto reductase-7A protects liver cells and tissues from acetaminophen-induced oxidative stress and hepatotoxicity.

• Ahmed MM, Wang T, Luo Y, Ye S, Wu Q, Guo Z, Roebuck BD, Sutter TR, Yang JY.SourceState Key Laboratory of Stress Cell Biology and Department of Biomedical Sciences, School of Life Sciences, Xiamen University, Xiamen 361005, China; Department of Biochemistry, Faculty of Medicine, Gadarif University, Gadarif 32211, Sudan.
• Hepatology (Baltimore, Md.).Hepatology.2011 Jun 17. doi: 10.1002/hep.24493. [Epub ahead of print]
• Aldo-keto reductase-7A (AKR7A) is an enzyme important for bioactivation and biodetoxification. Previous studies suggested that Akr7a might be transcriptionally regulated by oxidative stress-responsive transcription factor Nrf2, a protein highly responsive to acetaminophen (APAP) or its intermediate
• PMID 21688283

Japanese Journal

• 肝薬物代謝酵素の体内時計の分子機構を基盤にした投薬タイミング

• 松永 直哉
• YAKUGAKU ZASSHI 129(11), 1357-1365, 2009
• … Only a small portion of the dose is mainly bioactivated by CYP2E1 to N-acetyl-p-benzoquinone imine (NAPQI), a reactive toxic intermediate. … For APAP overdose, glucuronidation and sulfation are saturated and the formation of NAPQI increases. …
• NAID 130000136125

• Histopathological and Immunological Analysis of the Effects of Butylated Antioxidants on Acetaminophen - Hepatotoxity in Rats

• BOINDOGURONG Jinhua,EGASHIRA Yukari,SANADA Hiroo
• Journal of Oleo Science 55(10), 529-535, 2006
• … Acetaminophen (APAP) is mostly eliminated at a therapeutic dose through glucuronidation and sulfatation, while a small fraction is oxidized by cytochromes P450 (CYP) into N-acetyl-P-benzoquinone-imine (NAPQI). … NAPQI, a highly reactive metabolite of APAP is then conjugated with glutathione (GSH) and the product can be excreted into the urine. …
• NAID 130000055604

Related Links

• NAPQI - Wikipedia, the free encyclopedia

InChI=1S/C8H7NO2/c1-6(10)9-7-2-4-8(11)5-3-7/h2-5H,1H3 Yes Y Key: URNSECGXFRDEDC-UHFFFAOYSA-N Yes Y. N (what is this?) (verify). NAPQI ( N-acetyl-p-benzoquinone imine) is a toxic byproduct produced during the xenobiotic ...

Related Pictures

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★リンクテーブル★

リンク元	「アセトアミノフェン中毒」「N-アセチル-p-ベンゾキノンイミン」
関連記事	「NAP」

「アセトアミノフェン中毒」

　　[★]

英

acetaminophen poisoning

関

アセトアミノフェン N-acetyl-p-aminophenol、薬物性肝障害

概念

• アセトアミノフェンの大量摂取により生じる。

• 多くの薬に含まれており、意図せずにたくさん飲んでいることもある　→　規定量の数倍を飲むこともある
• 70kgの人 325mg x 20 中毒
• 　　　　　　　　 40 死

症状

• 1. ～数時間　嘔吐
• 2. 24時間　嘔吐、腹痛1
• 3. 2-5日　嘔吐、肝機能↓、黄疸、出血、熱
• 4. 5日以降　直るか肝不全となる

病態生理

参考1

• アセトアミノフェンは肝臓で硫酸基やグルクロン酸抱合をうけ、尿より排泄され、2%が代謝を受けずにそのまま排泄される。排泄されないアセトアミノフェンは混合機能オキシダーゼによりN-acetyl-p-benzoquinoneimine(NAPQI)に変換される。この物質は毒性が高い、反応性が高い、電子親和性が高いという特徴を有する。このNAPQIは肝臓のグルタチオンにより無毒化されて尿中に排泄される。
• 過剰量のアセトアミノフェンが投与された場合、NAPQIを無毒化するグルタチオンが消費される。肝臓のグルタチオンが70-80%まで消費されると、NAPQIは肝細胞と反応しこれを障害する。　→　肝細胞障害型の薬物性肝障害をきたす。

治療

• 直後：活性炭投与
• 初期：N-アセチルシステインの投与(グルタチオンの補給)。経口、静注、1-数日

参考

• 1. [charged] Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis - uptodate [1]

「N-アセチル-p-ベンゾキノンイミン」

　　[★]

英

N-acetyl-p-benzoquinoneimine, NAPQI

関

アセトアミノフェン、アセトアミノフェン中毒、グルタチオン

「NAP」

　　[★] 好中球アルカリホスファターゼ

関

NAPスコア、好中球アルカリホスファターゼスコア