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Trovafloxacin, a fluoroquinolone antibiotic with hepatotoxic potential, causes mitochondrial peroxynitrite stress in a mouse model of underlying mitochondrial dysfunction.
Chem Biol Interact 2010; 188(1):204-13CB

Abstract

Trovafloxacin (TVX) is a fluoroquinolone antibiotic whose therapeutic use was severely restricted due to an unacceptable risk of idiosyncratic liver injury. Oxidative stress and mitochondrial injury have been implicated in fluoroquinolone toxicity, but the mechanisms underlying liver injury are poorly understood. Because TVX-induced hepatotoxicity cannot be modeled in normal healthy rodents, we asked whether an underlying genetic defect (heterozygous deficiency in mitochondrial superoxide dismutase, Sod2) might aggravate TVX-induced mitochondrial adverse effects. Wild-type and Sod2(+/-) mice were treated with vehicle or alatrofloxacin (the prodrug of TVX, 33mg/kg/day, ip) for 28 days. We found that hepatic protein carbonyls were increased by 2.5-fold and hepatic mitochondrial aconitase activity was decreased by 20% in mutant, but not wild-type mice. Because aconitase is a major target of peroxynitrite, we determined the extent of nitrotyrosine residues in hepatic mitochondrial proteins. Trovafloxacin significantly increased nitrotyrosine in Sod2(+/-) mice only. Using the NO-selective probe DAF-2, we found that TVX increased the production of mitochondrial NO in immortalized human hepatocytes. Similarly, mitochondrial Ca(2+) was increased by TVX, suggesting Ca(2+)-dependent activation of mitochondrial NOS activity. Furthermore, the transcript levels of the mtDNA-encoded gene Cox2/mtCo2 were decreased in Sod2(+/-) mice only, while the expression of nDNA-encoded mitochondrial genes was not significantly altered in both genotypes, suggesting selective effects on mtDNA expression. The amount of mtDNA (copy number) was, however, unchanged. These data indicate that TVX enhances hepatic mitochondrial peroxynitrite stress in mice with underlying increased basal levels of superoxide, leading to the disruption of critical mitochondrial enzymes and gene regulation.

Authors+Show Affiliations

University of Connecticut, School of Pharmacy, Department of Pharmaceutical Sciences, Storrs, CT 06269-3092, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20655887

Citation

Hsiao, Chin-Ju J., et al. "Trovafloxacin, a Fluoroquinolone Antibiotic With Hepatotoxic Potential, Causes Mitochondrial Peroxynitrite Stress in a Mouse Model of Underlying Mitochondrial Dysfunction." Chemico-biological Interactions, vol. 188, no. 1, 2010, pp. 204-13.
Hsiao CJ, Younis H, Boelsterli UA. Trovafloxacin, a fluoroquinolone antibiotic with hepatotoxic potential, causes mitochondrial peroxynitrite stress in a mouse model of underlying mitochondrial dysfunction. Chem Biol Interact. 2010;188(1):204-13.
Hsiao, C. J., Younis, H., & Boelsterli, U. A. (2010). Trovafloxacin, a fluoroquinolone antibiotic with hepatotoxic potential, causes mitochondrial peroxynitrite stress in a mouse model of underlying mitochondrial dysfunction. Chemico-biological Interactions, 188(1), pp. 204-13. doi:10.1016/j.cbi.2010.07.017.
Hsiao CJ, Younis H, Boelsterli UA. Trovafloxacin, a Fluoroquinolone Antibiotic With Hepatotoxic Potential, Causes Mitochondrial Peroxynitrite Stress in a Mouse Model of Underlying Mitochondrial Dysfunction. Chem Biol Interact. 2010 Oct 6;188(1):204-13. PubMed PMID: 20655887.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Trovafloxacin, a fluoroquinolone antibiotic with hepatotoxic potential, causes mitochondrial peroxynitrite stress in a mouse model of underlying mitochondrial dysfunction. AU - Hsiao,Chin-Ju J, AU - Younis,Husam, AU - Boelsterli,Urs A, Y1 - 2010/07/23/ PY - 2010/05/18/received PY - 2010/07/14/revised PY - 2010/07/16/accepted PY - 2010/7/27/entrez PY - 2010/7/27/pubmed PY - 2010/10/5/medline SP - 204 EP - 13 JF - Chemico-biological interactions JO - Chem. Biol. Interact. VL - 188 IS - 1 N2 - Trovafloxacin (TVX) is a fluoroquinolone antibiotic whose therapeutic use was severely restricted due to an unacceptable risk of idiosyncratic liver injury. Oxidative stress and mitochondrial injury have been implicated in fluoroquinolone toxicity, but the mechanisms underlying liver injury are poorly understood. Because TVX-induced hepatotoxicity cannot be modeled in normal healthy rodents, we asked whether an underlying genetic defect (heterozygous deficiency in mitochondrial superoxide dismutase, Sod2) might aggravate TVX-induced mitochondrial adverse effects. Wild-type and Sod2(+/-) mice were treated with vehicle or alatrofloxacin (the prodrug of TVX, 33mg/kg/day, ip) for 28 days. We found that hepatic protein carbonyls were increased by 2.5-fold and hepatic mitochondrial aconitase activity was decreased by 20% in mutant, but not wild-type mice. Because aconitase is a major target of peroxynitrite, we determined the extent of nitrotyrosine residues in hepatic mitochondrial proteins. Trovafloxacin significantly increased nitrotyrosine in Sod2(+/-) mice only. Using the NO-selective probe DAF-2, we found that TVX increased the production of mitochondrial NO in immortalized human hepatocytes. Similarly, mitochondrial Ca(2+) was increased by TVX, suggesting Ca(2+)-dependent activation of mitochondrial NOS activity. Furthermore, the transcript levels of the mtDNA-encoded gene Cox2/mtCo2 were decreased in Sod2(+/-) mice only, while the expression of nDNA-encoded mitochondrial genes was not significantly altered in both genotypes, suggesting selective effects on mtDNA expression. The amount of mtDNA (copy number) was, however, unchanged. These data indicate that TVX enhances hepatic mitochondrial peroxynitrite stress in mice with underlying increased basal levels of superoxide, leading to the disruption of critical mitochondrial enzymes and gene regulation. SN - 1872-7786 UR - https://www.unboundmedicine.com/medline/citation/20655887/Trovafloxacin,_a_fluoroquinolone_antibiotic_with_hepatotoxic_potential,_causes_mitochondrial_peroxynitrite_stress_in_a_mouse_model_of_underlying_mitochondrial_dysfunction L2 - https://linkinghub.elsevier.com/retrieve/pii/S0009-2797(10)00474-6 DB - PRIME DP - Unbound Medicine ER -