Comparative hepatoprotective effects of tocotrienol analogs against drug-induced liver 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.

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.