The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity

Journal Article · Tue May 15 00:00:00 EDT 2012 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2012.03.012· OSTI ID:22215316

Henninger, Christian ^[1]; Huelsenbeck, Johannes; Huelsenbeck, Stefanie ^[1]; Grösch, Sabine ^[2]; Schad, Arno ^[3]; Lackner, Karl J. ^[4]; Kaina, Bernd ^[1]; Fritz, Gerhard ^[1]

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1. Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany)
2. Institute of Clinical Pharmacology, Johann Wolfgang Goethe University Frankfurt, Theodor Stern Kai 7, D-60590 Frankfurt/Main (Germany)
3. Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany)
4. Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany)

Liver is the main detoxifying organ and therefore the target of high concentrations of genotoxic compounds, such as environmental carcinogens and anticancer drugs. Here, we investigated the usefulness of lovastatin, which is nowadays widely used for lipid lowering purpose, as a hepatoprotective drug following the administration of the anthracycline derivative doxorubicin in vivo. To this end, BALB/c mice were exposed to either a single high dose or three consecutive low doses of doxorubicin. Acute and subacute hepatotoxicities were analyzed with or without lovastatin co-treatment. Lovastatin protected the liver against doxorubicin-induced acute pro-inflammatory and pro-fibrotic stress responses as indicated by an attenuated mRNA expression of tumor necrosis factor alpha (TNFα) and connective tissue growth factor (CTGF), respectively. Hepatoprotection by lovastatin was due to a reduced induction of DNA damage following doxorubicin treatment. The statin also mitigated subacute anthracycline-provoked hepatotoxicity as shown on the level of doxorubicin- and epirubicin-stimulated CTGF mRNA expression as well as histopathologically detectable fibrosis and serum concentration of marker enzymes of hepatotoxicity (GPT/GLDH). Kidney damage following doxorubicin exposure was not detectable under our experimental conditions. Moreover, lovastatin showed multiple inhibitory effects on doxorubicin-triggered hepatic expression of genes involved in oxidative stress response, drug transport, DNA repair, cell cycle progression and cell death. Doxorubicin also stimulated the formation of ceramides. Ceramide production, however, was not blocked by lovastatin, indicating that hepatoprotection by lovastatin is independent of the sphingolipid metabolism. Overall, the data show that lovastatin is hepatoprotective following genotoxic stress induced by anthracyclines. Based on the data, we hypothesize that statins might be suitable to lower hepatic injury following anthracycline-based anticancer therapy. -- Highlights: ► Normal tissue damage is the therapy limiting side effect of anthracyclines. ► The effect of lovastatin on doxorubicin-induced hepatic damage was analyzed in vivo. ► Lovastatin protects the liver against DNA damage induced by doxorubicin. ► Lovastatin protects against acute and subacute doxorubicin-induced hepatotoxicity. ► Hepatoprotection by lovastatin is independent of the shingolipid metabolism.

• OSTI ID: 22215316
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 1 Vol. 261; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
AMINOTRANSFERASES
APOPTOSIS
CARCINOGENS
CELL CYCLE
CONNECTIVE TISSUE
DNA
DNA REPAIR
DOXORUBICIN
ECOLOGICAL CONCENTRATION
ECR HEATING
FIBROSIS
GLUTATHIONE
GROWTH FACTORS
HEME
IN VIVO
INFLAMMATION
INJURIES
KIDNEYS
LIPIDS
LIVER
MESSENGER-RNA
METABOLISM
MICE
OXIDATION
PEROXIDASES
STRAND BREAKS
THERAPY
TRIOCTYLPHOSPHINE OXIDE