Zinc abrogates anticancer drug tamoxifen-induced hepatotoxicity by suppressing redox imbalance, NO/iNOS/NF-ĸB signaling, and caspase-3-dependent apoptosis in female rats.
Tamoxifen (TAM) is used in breast cancer chemotherapy since its approval by the Food and Drug Administration in 1977. However, TAM therapy is accompanied with hepatotoxicity - a source of worry to clinicians. Oxidative stress and inflammation are the major implicated mechanisms contributing to TAM hepatotoxicity. In this study, we explored whether zinc (Zn) supplementation could prevent TAM-induced hepatotoxicity in female Wistar rats. Rats were subjected to oral pretreatment of Zn (100 mg/kg body weight (b.w.)/day) for 14 days against hepatic toxicity induced by single intraperitoneal administration of TAM (50 mg/kg b.w.) on day 13. TAM markedly elevated serum liver enzymes, whereas total protein and albumin considerably reduced. TAM caused prominent depletion of hepatic-reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activity. Also, TAM significantly increased malondialdehyde (MDA) level. Further, it raised liver levels of tumor necrosis factor-α (TNF-α), interleukin-1β, (IL-1β), interleukin-6 (IL-6), and nitric oxide (NO) confirmed by the liver histopathological alterations. The mechanistic inflammatory expression of inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-ĸB), and expression of caspase-3 protein prominently increased. Zinc supplementation significantly modulated serum liver function markers, antioxidant enzymes, and GSH and MDA levels. Zinc downregulated the expression of cytokines, NO, iNOS, NF-ĸB and caspase-3, and ameliorated histopathological changes. Zinc protects against TAM-induced hepatotoxicity; it may serve as an adjuvant supplement for female patients undergoing TAM chemotherapy.
['Famurewa|Ademola C|AC|http://orcid.org/0000-0002-8795-9964', 'Ekeleme-Egedigwe|Chima A|CA|', 'David|Ebuka E|EE|', 'Eleazu|Chinedum O|CO|', 'Folawiyo|Abiola M|AM|', 'Obasi|Nwogo A|NA|']
D000818:Animals D000975:Antioxidants D017209:Apoptosis D056486:Chemical and Drug Induced Liver Injury D002712:Chlorides D016207:Cytokines D019587:Dietary Supplements D005260:Female D016328:NF-kappa B D009569:Nitric Oxide D052247:Nitric Oxide Synthase Type II D018384:Oxidative Stress D020011:Protective Agents D051381:Rats D017208:Rats, Wistar D015398:Signal Transduction D013629:Tamoxifen D017967:Zinc Compounds
zinc hepatotoxicity Tamoxifen chemotherapy oxidative stress inflammation