Novel protection by Omega-3-FAs (DHA or EPA) against carbamazepine's liver-injury: differential suppression of oxidative-stress and inflammatory markers, and the influence on carbamazepine-clearance

Summary: Purpose: Carbamazepine (CBZ)-evoked liver-injury is multifaceted and can be serious. Specific drug-antidote versus CBZ's hepatotoxicity has been absent. The effects of omega(ω)-3-FAs (Eicosapentaenoic acid, EPA, and Docosahexaenoic acid, DHA), on CBZ-toxicity, and possibly-involved mechanisms, have remained unknown. Here, we investigated whether and, how then, two-ω-3-FAs (DHA/EPA) may alleviate CBZ's hepatotoxicity, relieve the disrupted organelles of liver, and possibly alter CBZ-plasma levels. Methods: Rats were treated with CBZ (100 mg/kg orally, daily) for 1-2-weeks in the presence-and-absence of DHA (EPA). Biochemical-markers of hepatotoxicity (ALT, Albumin, ALP, γ-GT), oxidative-stress (MDA, GSH, TAC) and inflammation (IL-6, TNF-α, CRP) were assessed at one-week-intervals. Further, pharmacokinetic-studies assessed plasma-CBZ levels, with/without co-administered-ω-3-FAs, with immunoassays. Liver-histopathological sections were examined and correlated with functional and biochemical-markers. Results: either of the ω-3-FAs, DHA or EPA, in a rank-order of potency, significantly abolished all liver injury-markers, for oxidative-stress and inflammation. Kinetic-immunoassays revealed no interaction of DHA with serum-CBZ-levels. However, EPA significantly-increased CBZ-level than control. Histopathological-studies revealed only minimal portal inflammation with DHA. EPA, also, elicited additional degenerative-changes in the surrounding hepatocytes. Conclusions: ω-3-FAs mitigated CBZ-induced liver-toxicity by suppressing oxidative-stress and inflammation, without altering of its clearance, (DHA). EPA evoked a rise of plasma-CBZ levels and inferior-liver protection than DHA. Histopathological assessment showed ω-3-FAs to also protect liver-integrity and its organelles, thereby implying a fruitful therapeutic-regimen with CBZ.