ReviewPost ScreenThe heterozygous Sod2+/− mouse: modeling the mitochondrial role in drug toxicity
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 O2− 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.
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