Taurine zinc solid dispersions attenuate doxorubicin-induced hepatotoxicity and cardiotoxicity in rats.
The clinical efficacy of anthracycline anti-neoplastic agents is limited by cardiac and hepatic toxicities. The aim of this study was to assess the hepatoprotective and cardioprotective effects of taurine zinc solid dispersions, which is a newly-synthesized taurine zinc compound, against doxorubicin-induced toxicity in Sprague-Dawley rats intraperitoneally injected with doxorubicin hydrochloride (3mg/kg) three times a week (seven injections) over 28 days. Hemodynamic parameters, levels of liver toxicity markers and oxidative stress were assessed. Taurine zinc significantly attenuated the reductions in blood pressure, left ventricular pressure and ± dp/dtmax, increases in serum alanine aminotransferase and aspartate aminotransferase activities, and reductions in serum Zn(2+) and albumin levels (P<0.05 or 0.01) induced by doxorubicin. In rats treated with doxorubicin, taurine zinc dose-dependently increased liver superoxide dismutase activity and glutathione concentration, and decreased malondialdehyde level (P<0.01). qBase(+) was used to evaluate the stability of eight candidate reference genes for real-time quantitative reverse-transcription PCR. Taurine zinc dose-dependently increased liver heme oxygenase-1 and UDP-glucuronyl transferase mRNA and protein expression (P<0.01). Western blotting demonstrated that taurine zinc inhibited c-Jun N-terminal kinase phosphorylation by upregulating dual-specificity phosphoprotein phosphatase-1. Additionally, taurine zinc inhibited cardiomyocyte apoptosis as there was decreased TUNEL/DAPI positivity and protein expression of caspase-3. These results indicate that taurine zinc solid dispersions prevent the side-effects of anthracycline-based anticancer therapy. The mechanisms might be associated with the enhancement of antioxidant defense system partly through activating transcription to synthesize endogenous phase II medicine enzymes and anti-apoptosis through inhibiting JNK phosphorylation.
Lab of Traditional Chinese Medicine and Marine Drugs, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, Guangdong, China.
Yu
Y
Wang
Lab of Traditional Chinese Medicine and Marine Drugs, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, Guangdong, China.
Xueting
X
Mei
Lab of Traditional Chinese Medicine and Marine Drugs, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, Guangdong, China.
Jingquan
J
Yuan
Lab of Traditional Chinese Medicine and Marine Drugs, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, Guangdong, China.
Wenping
W
Lu
Lab of Traditional Chinese Medicine and Marine Drugs, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, Guangdong, China.
Binglong
B
Li
Lab of Traditional Chinese Medicine and Marine Drugs, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, Guangdong, China. Electronic address: Donghuixu007@163.com.
Donghui
D
Xu
D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D018943:Anthracyclines / Q000009:adverse effects; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D066126:Cardiotoxicity / Q000188:drug therapy*; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000009:adverse effects*; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D015778:Minor Histocompatibility Antigens; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013654:Taurine / Q000494:pharmacology*; D015854:Up-Regulation; D015032:Zinc / Q000494:pharmacology*; D000099148:UGT1A1 Enzyme
D000410:Alanine Transaminase; D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D001219:Aspartate Aminotransferases; D004317:Doxorubicin; D014453:Glucuronosyltransferase; D005978:Glutathione; D051547:Heme Oxygenase-1; D008315:Malondialdehyde; D015778:Minor Histocompatibility Antigens; D048055:Mitogen-Activated Protein Kinase 8; D012333:RNA, Messenger; D013654:Taurine; D015032:Zinc; C499946:Ugt1a1 protein, rat; D000099148:UGT1A1 Enzyme; C583026:glucuronosyltransferase 2B, rat
Apoptosis; Doxorubicin; Heme oxygenase-1; Taurine zinc solid dispersions; UDP-glucuronosyl transferase; c-Jun N-terminal kinase