title: Pattern recognition analysis for hepatotoxicity induced by acetaminophen using plasma and urinary 1H NMR-based metabolomics in humans.
abstract: Drug-induced liver injury (DILI) is currently an increasingly relevant health issue. However, available biomarkers do not reliably detect or quantify DILI risk. Therefore, the purpose of this study was to comparatively evaluate plasma and urinary biomarkers obtained from humans treated with acetaminophen (APAP) using a metabolomics approach and a proton nuclear magnetic resonance (NMR) platform. APAP (3 g/day, two 500 mg tablets every 8 h) was administered to 20 healthy Korean males (age, 20-29 years) for 7 days. Urine was collected daily before and during dosing and 6 days after the final dose. NMR spectra of these urine samples were analyzed using principal component analysis (PCA) and partial least-squares-discrimination analysis. Although the activities of aspartate aminotransferase and lactate dehydrogenase were significantly increased 7 days post-APAP treatment, serum biochemical parameters of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, γ-glutamyl transpeptidase, and lactate dehydrogenase were within normal range of hepatic function. However, urine and plasma (1)H NMR spectroscopy revealed different clustering between predosing and after APAP treatment for global metabolomic profiling through PCA. Urinary endogenous metabolites of trimethylamine-N-oxide, citrate, 3-chlorotyrosine, phenylalanine, glycine, hippurate, and glutarate as well as plasma endogenous metabolites such as lactate, glucose, 3-hydroxyisovalerate, isoleucine, acetylglycine, acetone, acetate, glutamine, ethanol, and isobutyrate responded significantly to APAP dosing in humans. Urinary and plasma endogenous metabolites were more sensitive than serum biochemical parameters. These results might be applied to predict or screen potential hepatotoxicity caused by other drugs using urinary and plasma (1)H NMR analyses.
authors.affiliation: Department of Smart Food and Drug, Inje University , Obang-dong, Gimhae, Gyungnam 621-749, Republic of Korea.
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Kim
authors.forename: Sung Ha
authors.initials: SH
authors.lastname: Ryu
authors.forename: Siwon
authors.initials: S
authors.lastname: Kim
authors.forename: Hae Won
authors.initials: HW
authors.lastname: Lee
authors.forename: Mi-sun
authors.initials: MS
authors.lastname: Lim
authors.forename: Sook Jin
authors.initials: SJ
authors.lastname: Seong
authors.forename: Suhkmann
authors.initials: S
authors.lastname: Kim
authors.forename: Young-Ran
authors.initials: YR
authors.lastname: Yoon
authors.forename: Kyu-Bong
authors.initials: KB
authors.lastname: Kim
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects / Q000097:blood* / Q000652:urine*; D000328:Adult; D015415:Biomarkers / Q000097:blood / Q000652:urine; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000453:epidemiology / Q000652:urine*; D006801:Humans; D006859:Hydrogen; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D055432:Metabolomics / Q000379:methods*; D008875:Middle Aged; D010363:Pattern Recognition, Automated / Q000379:methods; D056910:Republic of Korea / Q000453:epidemiology; D055815:Young Adult
chemical_list: D015415:Biomarkers; D000082:Acetaminophen; D006859:Hydrogen