Threadgill1: Drug study: Toxicogenetic survey of susceptibility to acetaminophen-induced liver injury in males of 37 inbred strains of mice (2005)

Harrill AH, Watkins PB, Su S, Ross PK, Harbourt DE, Stylianou IM, Boorman GA, Russo MW, Sackler RS, Harris SC, Smith PC, Tennant R, Bogue M, Paigen K, Harris C, Contractor T, Wiltshire T, Rusyn I, Threadgill DW. Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans. Genome Res. 2009 Sep;19(9):1507-15. Epub 2009 May 5.   PubMed 19416960     FullText

Harrill AH, Ross PK, Gatti DM, Threadgill DW, Rusyn I. Population-based discovery of toxicogenomics biomarkers for hepatotoxicity using a laboratory strain diversity panel. Toxicol Sci. 2009 Jul;110(1):235-43. Epub 2009 May 6.   PubMed 19420014     FullText


       
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Participants David W Threadgill       Texas A&M University College Station, TX
Alison Harrill       University of Arkansas for Medical Sciences Little Rock, AR
Ivan Rusyn       Texas A&M University College Station, TX
With: Ross PK
ContactDavid W Threadgill     dwthreadgill@tamu.edu     Lab web site
Part of a series: • Phase 1   (this project) Threadgill1
• Phase 2   see Threadgill2
AcknowledgementsFunding provided by NIH ES07126, ES11391, ES10126, GM38149, RR00046, ES35513, ES25497, ES65406; US Environmental Protection Agency STAR-RD832720

For technical assistance and histology: Balletta L, Bradford B, Lodestro C, Lee D, Maki A, Kosyk O, Woods C, Clore E, Hodges N, Boorman G. For serum enzyme testing: Kim H and the Clinical Chemistry Core Facility (UNC).
Project type Phenotype strain survey data set
MPD identifiersThreadgill1     MPD:194
Data changelog 1 update/correction.       Initial release date: 02/2009.
Formatted citation
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An investigation of liver injury after administration of acetaminophen (N-acetyl-p-aminophenol; APAP) in various doses. The study involved 8 cohorts, including controls as well as animals treated with acetaminophen 30, 100, 200, 300, 600, 900, and 1200 mg/kg body weight. Animals were evaluated in these areas: blood and liver chemistry, liver function, and alterations in liver morphology. Data are presented here for selected cohorts and measurements.

Summary of procedures that were conducted
• metabolic panel Blood urea nitrogen, alanine transaminase, aspartate transaminase (serum), liver enzyme homeostasis. Acetaminophen (several doses) vs. control, several timepoints post-Rx. 18h fast.
• histopathology Liver histopathology, necrosis after acetaminophen vs. control. 18h fast.
• metabolite quantification Liver protein homeostasis. Acetaminophen vs. control. 18h fast.
• biomarker quantification Liver cytochrome isoforms. Acetaminophen vs. control. 18h fast.
• organ weights Liver weight after acetaminophen (several doses) vs. control. 18h fast.
Mice: inbred   37 strains   ♂   age 8-17wks   8 cohorts

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Data set MPD ID Procedure / Protocol Drug or Challenge Phenotype Measure Panel No. of Strains Sex Age Sample Size (Avg)
    Threadgill1 19401 organ weights acetaminophen liver weight   [g]     control    24h post-Rx mg/kg:    100    200    300 inbred w/CC7 37 m 8-17wks N=4
    Threadgill1 19404 histopathology acetaminophen necrosis   [%]     control    post-Rx mg/kg:    100    200    300 inbred w/CC7 37 m 8-17wks N=3
    Threadgill1 19406 metabolic panel acetaminophen  control alanine transaminase (serum ALT)   [IU/L]  ALT_ctrl inbred w/CC7 37 m 8-17wks N=2
    Threadgill1 19407 metabolic panel acetaminophen  100mg/kg alanine transaminase (serum ALT), t=4h   [IU/L]  ALT_Rx100_4h inbred 7 m 8-17wks N=4
    Threadgill1 19408 metabolic panel acetaminophen  100mg/kg alanine transaminase (serum ALT), t=12h   [IU/L]  ALT_Rx100_12h inbred 7 m 8-17wks N=4
    Threadgill1 19409 metabolic panel acetaminophen  100mg/kg alanine transaminase (serum ALT), t=24h   [IU/L]  ALT_Rx100_24h inbred 7 m 8-17wks N=3
    Threadgill1 19410 metabolic panel acetaminophen aspartate transaminase (serum AST)   [IU/L]     control    post-Rx mg/kg:    100    200    300 inbred w/CC7 37 m 8-17wks N=3
    Threadgill1 19412 metabolic panel acetaminophen blood urea nitrogen (BUN)   [mg/dL]     control    post-Rx mg/kg:    100    200    300 inbred w/CC7 36 m 8-17wks N=3
    Threadgill1 19414 metabolite quantification acetaminophen reduced glutathione (GSH)   [µmol/g]     control    post-Rx 300mg/kg inbred w/CC7 35 m 8-17wks N=3
    Threadgill1 19416 metabolite quantification acetaminophen oxidized glutathione (GSSG)   [µmol/g]     control    post-Rx 300mg/kg inbred w/CC7 35 m 8-17wks N=3
    Threadgill1 19418 metabolite quantification acetaminophen total glutathione (GSH plus GSSG)   [µmol/g]     control    post-Rx 300 mg/kg inbred w/CC7 35 m 8-17wks N=3
    Threadgill1 19420 metabolite quantification acetaminophen ratio of reduced (GSH) to oxidized (GSSG) glutathione   [ratio]     control    post-Rx 300mg/kg inbred w/CC7 35 m 8-17wks N=3
    Threadgill1 19482 metabolic panel acetaminophen catalase   [µg/mL]     control    post-Rx 300 mg/kg inbred w/CC7 37 m 8-12wks N=3
    Threadgill1 19483 biomarker quantification acetaminophen cytochrome P450 1A2 isoform   [pmol/mg]     control    post-Rx 300 mg/kg inbred 36 m 8-12wks N=3
    Threadgill1 19484 biomarker quantification acetaminophen cytochrome P450 2E1 isoform   [pmol/mg]     control    post-Rx 300 mg/kg inbred w/CC7 37 m 8-12wks N=3
    Threadgill1 19486 metabolite quantification acetaminophen glutathione transferase   [µg/mL]     control    post-Rx 300 mg/kg inbred w/CC7 37 m 8-12wks N=3
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