title: A 1H NMR-based metabolomics approach for mechanistic insight into acetaminophen-induced hepatotoxicity.
abstract: The widely used analgesic-antipyretic drug acetaminophen (APAP) is known to cause serious liver necrosis at high doses in man and experimental animals. For studies of toxic processes, 1H NMR spectroscopy of biofluids allows monitoring of endogenous metabolite profiles that alter characteristically in response to changes in physiological status. Herein, a 1H NMR metabolomics approach was applied to the investigation of APAP toxicity in rats and the effect of phenobarbital (PB) on APAP-induced hepatotoxicity. Metabolite differences due to hepatotoxicity were observed in 1H NMR spectra of serum and urine, and enhanced APAP hepatotoxicity by pretreatment with PB was clearly shown by a principal components analysis of the spectral data. NMR spectra of APAP-dosed rat urine provided profiles of APAP-related compounds together with endogenous metabolites. By comparison of endogenous and APAP-related metabolite spectra with those from rats pretreated with PB, it was possible to show the importance of oxidative metabolism of APAP to N-acetyl-p-benzoquinone, an essential step in APAP hepatotoxicity.
authors.affiliation: Division of Organic Chemistry, National Institute of Health Sciences, Tokyo, Japan. fukuhara@nihs.go.jp
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Fukuhara
authors.forename: Akiko
authors.initials: A
authors.lastname: Ohno
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ando
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamoto
authors.forename: Haruhiro
authors.initials: H
authors.lastname: Okuda
mesh_terms: D000082:Acetaminophen / Q000097:blood / Q000378:metabolism* / Q000633:toxicity* / Q000652:urine; D018712:Analgesics, Non-Narcotic / Q000097:blood / Q000378:metabolism* / Q000633:toxicity* / Q000652:urine; D000818:Animals; D016227:Benzoquinones / Q000097:blood / Q000378:metabolism / Q000633:toxicity / Q000652:urine; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D004790:Enzyme Induction; D005978:Glutathione / Q000097:blood / Q000378:metabolism / Q000633:toxicity / Q000652:urine; D007097:Imines / Q000097:blood / Q000378:metabolism / Q000633:toxicity / Q000652:urine; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D055432:Metabolomics; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010634:Phenobarbital / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D018712:Analgesics, Non-Narcotic; D016227:Benzoquinones; D007097:Imines; D000082:Acetaminophen; C028473:N-acetyl-4-benzoquinoneimine; D005978:Glutathione; D010634:Phenobarbital