Comparative hepatoprotective effects of tocotrienol analogs against drug-induced liver injury
| Autor: | Chee Wai Fong, Cheau Yih Tan, Han Kiat Ho, Tzuen Yih Saw |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
PMSF
phenylmethanesulfonyl fluoride Drug-induced liver injury medicine.medical_treatment Clinical Biochemistry Nitric Oxide Synthase Type II Tocopherols DMEM/F12 Dulbecco’s modified Eagle's medium/Ham's F12 Pharmacology medicine.disease_cause Biochemistry Antioxidants ITS insulin transferrin selenium Lipid peroxidation chemistry.chemical_compound Mice MTT 3-(4 5-dimethylthiazol-2-yl)-2 5-diphenyltetrazolium bromide MPT membrane potential transition GST glutathione-s-transferase Vitamin E TNF-α tumor necrosis factor alpha PMC 2 2 5 7 8-pentamethyl-6-chromal lcsh:QH301-705.5 Cell Line Transformed Liver injury lcsh:R5-920 Tocopherol Chemistry Caspase 3 qRT-PCR quantitative real time-polymerase chain reaction NAPQI N-acetyl-p-benzoquinoneimine TGF-α transforming growth factor alpha Liver regeneration Mitochondria DILI drug-induced liver injury HPLC high performance liquid chromatography H2O2 hydrogen peroxide mrpw multiple reads per well iNOS inducible nitric oxide synthase LPO lipid peroxidation Tocotrienol HO-1 Heme oxygenase-1 Antioxidant lcsh:Medicine (General) medicine.drug Signal Transduction Research Paper DMSO dimethylsulfoxide NAPQI DAD diode array detector Cell Survival PCNA proliferating cell nuclear antigen bcl-X Protein APAP acetaminophen FLD fluorescence detector Protective Agents Nrf-2 nuclear factor erythroid 2-related factor ROS reactive oxygen species PBS phosphate buffered saline Proliferating Cell Nuclear Antigen medicine Animals IL-6 interleukin 6 (IL-6) Hepatoprotective Agent Acetaminophen Interleukin-6 Tumor Necrosis Factor-alpha Organic Chemistry MCB monochlorobimane GSH L-glutathione reduced Hydrogen Peroxide α-T3 α-tocotrienol medicine.disease TP tocopherol SEM standard error of means Oxidative Stress T3 tocotrienol Gene Expression Regulation lcsh:Biology (General) Hepatocytes α-TP α-tocopherol BSA bovine serum albumin Lipid Peroxidation Reactive Oxygen Species Oxidative stress |
| Zdroj: | Redox Biology, Vol 4, Iss C, Pp 308-320 (2015) Redox Biology |
| ISSN: | 2213-2317 |
| Popis: | Oxidative stress plays a major part in the pathogenesis of drug-induced liver injury. Yet, overcoming it with other xenobiotics impose additional risks. In this study, we consider the use of natural-occurring and purified Vitamin E analogs as hepatoprotective agents. Vitamin E is well-known for its intrinsic antioxidant property even though the differential effect of specific analogs of tocopherol (TP) and tocotrienol (T3) is still not ascertained. This study investigates the protective effect of T3 analogs (α-, δ-, γ−) in comparison with α-TP followed by assessing the underlying mechanisms of the cytoprotective T3 analog(s) in two xenobiotics-induced liver injury models using (1) acetaminophen (APAP)- and (2) hydrogen peroxide (H2O2). Both α-TP and α-T3 exerted cytoprotective effects while only lower concentration of γ-T3 was effective in inhibiting both toxicants induced injury. α-TP/α-T3 protected hepatocytes from APAP and H2O2-induced liver injury through arresting free radicals and inhibiting oxidative stress (inhibition of reactive oxygen species, lipid peroxidation and mitochondrial permeability transition). There was also demonstrable inhibition of the apoptotic pathway (inhibition of caspse-3 activity and overexpression of Bcl-XL), accompanied with an induction of liver regeneration (PCNA and NF-kB). The cellular uptake of α-T3 was higher than α-TP at the same treatment dosage after 24 h. Overall, α-T3 seems to be a more potent hepatoprotective analog among the tocotrienols and α-TP at the same in vitro treatment dosage. In summary, these results suggest that α-TP/α-T3 elicit hepatoprotective effects against toxicants-induced damage mainly through activation of antioxidant responses at an early stage to prevent the exacerbation of injury. Research highlights • Purified T3 analogs were compared for their hepatoprotective effects against two toxicants-induced liver injuries. • α-TP/α-T3 and lower concentration of γ-T3 exerted significant cytoprotective effects. • α-TP/α-T3 inhibits oxidative stress and apoptosis while induces liver regeneration. • α-T3 is the most potent hepatoprotective analog among T3 and α-TP at same dose. • α-TP/α-T3 prevented toxicants-induced injury mainly through antioxidant responses. |
| Databáze: | OpenAIRE |
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