Elsevier

Drug Discovery Today

Volume 13, Issues 21–22, November 2008, Pages 982-988
Drug Discovery Today

Review
Post Screen
The heterozygous Sod2+/− mouse: modeling the mitochondrial role in drug toxicity

https://doi.org/10.1016/j.drudis.2008.08.002Get rights and content

Mitochondria have been increasingly implicated in being a crucial subcellular target and amplifying oxidative injury induced by many drugs. Among the major cytoprotective antioxidants is the mitochondrial matrix protein, superoxide dismutase-2 (SOD2). Genetic modification of the expression of SOD2 by transgenic techniques or gene silencing has generated a number of distinct animal models with SOD2 deficiency including the heterozygous Sod2+/− knockout mouse model. These mice display a discreet underlying mitochondrial stress but are otherwise phenotypically normal and thus model a variety of clinically silent mitochondrial abnormalities. The model has found application in oxidative stress and age-related research, but it is only recently that it has been successfully used to study mechanisms of idiosyncratic drug-induced liver injury.

Section snippets

Introduction: role of mitochondria in drug toxicity

Mitochondrial dysfunction is a frequent off-target effect of a large number of drugs, a well-known finding that has gained renewed appreciation in recent years 1, 2, 3, 4, 5, 6. The most sensitive organs of mitochondrial toxicity are cardiac muscle and the central nervous system, but skeletal muscle, liver, and kidney can also be affected. These adverse drug effects are, however, not always obvious in preclinical studies, as most cells harbor hundreds or thousands of individual mitochondria

Animal models of drug-induced oxidant stress and mitochondrial injury

There are three types of animal models that have been used to study the role of mitochondrial dysfunction in organ damage [18]. Firstly, in certain cases, it has been possible to use standard drugs and induce an organ-selective toxic response in rodents that is clearly due to mitochondrial injury. Well-known examples include high-dose acetaminophen-induced hepatic necrosis in sensitive mouse strains 19, 20, 21 or doxorubicin-induced cardiac toxicity in rats [22]. Besides these isolated cases,

Superoxide dismutase-2

Superoxide dismutase (SOD) is an important enzyme that converts two superoxide molecules to hydrogen peroxide and molecular oxygen by dismutation (e.g. one molecule of O2radical dot is oxidized while the second one is reduced). There are several forms of this protein in mammals, SOD1, 2, and 3. SOD1 (Cu, ZnSOD) is abundant in the cytosol and in the intermembrane space of mitochondria [31]. In mitochondria, SOD1 has recently been shown to cooperate with cytochrome c to trigger apoptosis upon leaking out

The heterozygous Sod2+/− mouse model

Heterozygous animals have recently been recognized to provide alternative and novel genetic mouse models beyond knockouts [54]. As compared with the null-mice, heterozygous animals not only can display intermediate phenotypes but they can also exhibit principally new phenotypes. For Sod2, heterozygous deficiency leads to a much more discreet phenotype than that of the homozygously deficient mice. Mutant Sod2+/− mice proved to have a similar body weight and growth rate as wild-type controls and

Application of the heterozygous Sod2+/− mouse model in drug safety studies

Sod2-transgenic and mutant mice have been used in the past to study the effects of increased ROS production 36, 51. For example, 50% deficiency in SOD2 exacerbates oxidant stress-dependent cerebral infarction following ischemia [59]. By implication, drugs or other chemicals that generate increased oxidant stress would have a much greater effect in the heterozygous Sod2+/− mouse model than in wild-type mice. Indeed, the heterozygous phenotype primed liver mitochondria to the prooxidant effects

Conclusions

Murine models in which SOD2 has been modified by transgenic techniques, conditional knockout, or gene silencing approaches not only lend themselves for the study of mitochondrial oxidant stress, disease, or aging but also have been increasingly recognized as potential models that modulate drug-induced organ toxicity. Potential new applications of this paradigm will undoubtedly go beyond hepatotoxicity and include other organs such as the heart, brain, or skeletal muscle, but currently I-DILI is

Acknowledgements

This work was supported by the Boehringer Ingelheim Endowed Chair in Mechanistic Toxicology at the University of Connecticut and a research grant from Pfizer, Inc.

References (77)

  • K.B. Choksi et al.

    Age-related alterations in oxidatively damaged proteins of mouse heart mitochondrial electron transport chain complexes

    Free Radic. Biol. Med.

    (2008)
  • K. Nakada

    Mito-mice: animal models for mitochondrial DNA-based diseases

    Sem. Cell Dev. Biol.

    (2001)
  • C.A. Pinkert et al.

    Production of transmitochondrial mice

    Methods

    (2002)
  • A. Okado-Matsumoto et al.

    Subcellular distribution of superoxide dismutase (SOD) in rat liver. Cu, Zn-SOD in mitochondria

    J. Biol. Chem.

    (2001)
  • Q. Li

    A possible cooperation of SOD1 and cytochrome c in mitochondria-dependent apoptosis

    Free Radic. Biol. Med.

    (2006)
  • G.R. Buettner

    A new paradigm: manganese superoxide dismutase influences the production of H2O2 in cells and thereby their biological state

    Free Radic. Biol. Med.

    (2006)
  • W. Beyer

    Superoxide dismutases

    Prog. Nucleic Acid Res. Mol. Biol.

    (1991)
  • H. Goto

    Endothelial MnSOD overexpression prevents retinal VEGF expression in diabetic mice

    Biochem. Biophys. Res. Commun.

    (2008)
  • S.I. Liochev et al.

    The effects of superoxide dismutase on H2O2 formation

    Free Radic. Biol. Med.

    (2007)
  • R. Gardner

    Why does SOD overexpression sometimes enhance, sometimes decrease, hydrogen peroxide production? A minimalist explanation

    Free Radic. Biol. Med.

    (2002)
  • A. Vasilaki

    Genetic modification of the manganese superoxide dismutase/glutathione peroxidase 1 pathway influences intracellular ROS generation in quiescent, but not contracting, skeletal, muscle cells

    Free Radic. Biol. Med.

    (2006)
  • T.T. Huang

    Genetic modification of prenatal lethality and dilated cardiomyopathy in Mn superoxide dismutase mutant mice

    Free Radic. Biol. Med.

    (2001)
  • K.J. Morten

    Mitochondrial reactive oxygen species in mice lacking superoxide dismutase 2

    J. Biol. Chem.

    (2006)
  • T. Ikegami

    Model mice for tissue-specific deletion of the manganese superoxide dismutase (MnSOD) gene

    Biochem. Biophys. Res. Commun.

    (2002)
  • A.V. Kalueff

    The developing use of heterozygous mutant mouse models in brain monoamine transporter research

    Trends Pharmacol. Sci.

    (2007)
  • H. Van Remmen

    Characterization of the antioxidant status of the heterozygous manganese superoxide dismutase knockout mouse

    Arch. Biochem. Biophys.

    (1999)
  • M.D. Williams

    Increased oxidative damage is correlated to mitochondrial function in heterozygous manganese dismutase knockout mice

    J. Biol. Chem.

    (1998)
  • L.P. Liang et al.

    Mitochondrial oxidative stress and increased seizure susceptibility in Sod2−/+ mice

    Free Radic. Biol. Med.

    (2004)
  • H. Van Remmen

    Multiple deficiencies in antioxidant enzymes in mice result in a compound increase in sensitivity to oxidative stress

    Free Radic. Biol. Med.

    (2004)
  • G. Cortopassi et al.

    Modelling the effects of age-related mtDNA mutation accumulation: complex I deficiency, superoxide and cell death

    Biochim. Biophys. Acta

    (1995)
  • V. Adam-Vizi et al.

    Bioenergetics and the formation of mitochondrial reactive oxygen species

    Trends Pharmacol. Sci.

    (2006)
  • M.M.K. Ong

    Nimesulide-induced hepatic mitochondrial injury in heterozygous Sod2+/− mice

    Free Radic. Biol. Med.

    (2006)
  • Y.H. Lee

    Troglitazone-induced hepatic mitochondrial proteome expression dynamics in heterozygous Sod2+/− mice: two-stage oxidative injury

    Toxicol. Appl. Pharmacol

    (2008)
  • I.N. Zelko

    Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression

    Free Radic. Biol. Med.

    (2002)
  • S. Shimoda-Matsubayashi

    Structural dimorphism in the mitochondrial targeting sequence in the human manganese superoxide dismutase gene. A predictive evidence for conformational change to influence mitochondrial transport and a study of allelic association in Parkinson's disease

    Biochem. Biophys. Res. Commun.

    (1996)
  • P. Nahon

    Genetic dimorphism in superoxide dismutase and susceptibility to alcoholic cirrhosis, hepatocellular carcinoma, and death

    Clin. Gastroenterol. Hepatol.

    (2005)
  • Y.S. Huang

    Genetic polymorphisms of manganese superoxide dismutase, NAD(P)H:quinone oxidoreductase, glutathione S-transferase M1 and T1, and the susceptibility to drug-induced liver injury

    J. Hepatol.

    (2007)
  • S. Lynn

    Selective neuronal vulnerability and inadequate stress response in superoxide dismutase mutant mice

    Free Radic. Biol. Med.

    (2005)
  • Cited by (37)

    • Drug-induced oxidative stress as a mechanism of toxicity

      2023, Essentials of Pharmatoxicology in Drug Research: Toxicity and Toxicodynamics: Volume 1
    • Genetically Engineered Animal Models in Toxicologic Research

      2021, Haschek and Rousseaux's Handbook of Toxicologic Pathology: Volume 1: Principles and Practice of Toxicologic Pathology
    • Superoxide Dismutase 1 Protects Hepatocytes from Type I Interferon-Driven Oxidative Damage

      2015, Immunity
      Citation Excerpt :

      This coincided with our observation that infection with LCMV resulted in a downregulation of SOD1 expression at the RNA (Figures 1D and 1E) and protein level (Figure 1F). To investigate whether SOD enzymes contribute to viral hepatitis, we infected Sod1−/−, Sod2+/−—a commonly used model for Sod2 deficiency (Boelsterli and Hsiao, 2008)—and Sod3−/− mice with LCMV and monitored the course of disease. Sod1−/− but not Sod2+/− or Sod3−/− mice lost more body weight compared to WT mice, which started in the early phase of infection (Figure 2A, Figure S1A).

    • Genetically Engineered Animals in Product Discovery and Development

      2013, Haschek and Rousseaux's Handbook of Toxicologic Pathology
    View all citing articles on Scopus
    View full text