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Research ArticleArticle

A High Dose of Isoniazid Disturbs Endobiotic Homeostasis in Mouse Liver

Feng Li, Pengcheng Wang, Ke Liu, Mariana G. Tarrago, Jie Lu, Eduardo N. Chini and Xiaochao Ma
Drug Metabolism and Disposition November 2016, 44 (11) 1742-1751; DOI: https://doi.org/10.1124/dmd.116.070920
Feng Li
Department of Molecular and Cellular Biology, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas (F.L.); Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (P.W., K.L., J.L., X.M.), Laboratory of Signal Transduction, Department of Anesthesiology and Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, Minnesota (M.G.T., E.N.C.)
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Pengcheng Wang
Department of Molecular and Cellular Biology, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas (F.L.); Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (P.W., K.L., J.L., X.M.), Laboratory of Signal Transduction, Department of Anesthesiology and Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, Minnesota (M.G.T., E.N.C.)
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Ke Liu
Department of Molecular and Cellular Biology, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas (F.L.); Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (P.W., K.L., J.L., X.M.), Laboratory of Signal Transduction, Department of Anesthesiology and Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, Minnesota (M.G.T., E.N.C.)
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Mariana G. Tarrago
Department of Molecular and Cellular Biology, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas (F.L.); Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (P.W., K.L., J.L., X.M.), Laboratory of Signal Transduction, Department of Anesthesiology and Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, Minnesota (M.G.T., E.N.C.)
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Jie Lu
Department of Molecular and Cellular Biology, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas (F.L.); Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (P.W., K.L., J.L., X.M.), Laboratory of Signal Transduction, Department of Anesthesiology and Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, Minnesota (M.G.T., E.N.C.)
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Eduardo N. Chini
Department of Molecular and Cellular Biology, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas (F.L.); Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (P.W., K.L., J.L., X.M.), Laboratory of Signal Transduction, Department of Anesthesiology and Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, Minnesota (M.G.T., E.N.C.)
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Xiaochao Ma
Department of Molecular and Cellular Biology, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas (F.L.); Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (P.W., K.L., J.L., X.M.), Laboratory of Signal Transduction, Department of Anesthesiology and Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, Minnesota (M.G.T., E.N.C.)
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  • Fig. 1.
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    Fig. 1.

    Metabolomic analysis of mouse liver from the control and INH-treated groups. Wild-type mice were treated with vehicle or 200 mg/kg INH (by mouth). Liver samples were collected 30 minutes after treatment. All samples were analyzed by UPLC-QTOFMS. (A) Separation of control and INH-treated groups in a PCA score plot. The t[1] and t[2] values represent the score of each sample in principal components 1 and 2, respectively. (B) Loading S-plot generated by orthogonal projection to latent structures discriminant analysis. w[1]P, measure of the relative abundance of ions; p(corr)[1]P, measure of the correlation of each ion to the model.

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    Fig. 2.

    Accumulation of heme (I) in the livers of mice treated with INH. (A) The extracted chromatogram of heme. (B) MS/MS findings of heme. (C) Relative abundance of heme. The data are expressed as the mean ± SEM (n = 3). ***p < 0.001 versus control group.

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    Fig. 3.

    Accumulation of oleoyl-l-carnitine (II) and linoleoyl-l-carnitine (metabolite III) in the livers of mice treated with INH. (A) Extracted chromatograms of acylcarnitines II and III. (B) MS/MS findings of oleoyl-l-carnitine (II). (C) MS/MS findings of linoleoyl-l-carnitine (III). (D) Relative abundance of acylcarnitines II and III in the liver. The data are expressed as the mean ± SEM (n = 3). **p < 0.01, ***p < 0.001 versus control group.

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    Fig. 4.

    Formation of INH-fatty acid amides (IV and V). (A) Extracted chromatograms of amides IV and V. (B) MS/MS findings of amide IV. (C) MS/MS findings of amide V. (D) Relative abundance of amides IV and V. The data are expressed as the mean ± SEM (n = 3). **p < 0.01 versus control group. (E) The scheme of the formation of INH-fatty acid amides. N.D., not detected.

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    Fig. 5.

    Accumulation of NAD (VI) in the livers of mice treated with INH. (A) MS/MS findings of NAD. (B) Relative abundance of NAD in the liver. The data are expressed as the mean ± SEM (n = 3). ***p < 0.001 versus control group. (C) The inhibitory effect of INH on NADase activity.

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    Fig. 6.

    Formation of INH-NAD adduct (VII) in the livers of mice treated with INH. (A) MS/MS findings of INH-NAD adduct. (B) MS/MS findings of d4-INH-NAD adduct. (C) Relative abundance of INH-NAD adduct in the liver. (D) The role of NADase in the formation of INH-NAD adduct. The quantified data are expressed as the mean ± SEM (n = 3). N.D., not detected. ***p < 0.001 versus control group.

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    Fig. 7.

    Accumulation of cystathionine (VIII) in the livers of mice treated with INH. (A) The extracted chromatogram of cystathionine from the liver. (B) MS/MS findings of cystathionine. (C) Relative abundance of cystathionine in the liver. (D) MS/MS findings of INH-PL adduct. (E) Relative abundance of PLP in the liver. All quantified data are expressed as the mean ± SEM (n = 3). **p < 0.01, ***p < 0.001 versus control group. (F) The proposed mechanism by which INH disturbs cystathionine homeostasis. CSE, cystathionine gamma-lyase.

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    Fig. 8.

    The scheme of disturbance of endogenous pathways in mouse liver by a high dose of INH. FA, fatty acid.

Additional Files

  • Figures
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    Files in this Data Supplement:

    • Supplemental Data -

      Supplemental Table 1 - The top ranking ions in the serum of mice treated with INH

      Supplemental Figure 1 - Metabolomic analysis of mouse serum from the control and INH-treated groups

      Supplemental Figure 2 - Biochemical analysis of serum ALT (A) and AST (B) activities in mice treated with INH

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Drug Metabolism and Disposition: 44 (11)
Drug Metabolism and Disposition
Vol. 44, Issue 11
1 Nov 2016
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Research ArticleArticle

Acute Effect of Isoniazid on Liver Metabolome

Feng Li, Pengcheng Wang, Ke Liu, Mariana G. Tarrago, Jie Lu, Eduardo N. Chini and Xiaochao Ma
Drug Metabolism and Disposition November 1, 2016, 44 (11) 1742-1751; DOI: https://doi.org/10.1124/dmd.116.070920

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Research ArticleArticle

Acute Effect of Isoniazid on Liver Metabolome

Feng Li, Pengcheng Wang, Ke Liu, Mariana G. Tarrago, Jie Lu, Eduardo N. Chini and Xiaochao Ma
Drug Metabolism and Disposition November 1, 2016, 44 (11) 1742-1751; DOI: https://doi.org/10.1124/dmd.116.070920
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