Original Article
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

https://doi.org/10.1016/j.nutos.2022.01.006Get rights and content
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Highlights

  • Though carbamazepine (CBZ)'s liver-injury is serious; it has no specific antidote.

  • Whether omega-3-FAs, DHA/EPA, would abate CBZ's toxicity, and how, remained vague.

  • We checked markers of oxidative stress and inflammation with CBZ (+/-) DHA or EPA.

  • DHA > EPA, markedly sank CBZ's histopathology, oxidative stress and inflammation.

  • EPA, unlike DHA, markedly rose CBZ-clearance, thus reflecting kinetic interaction.

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.

Graphical abstract

Whether, and how/mechanisms, the ω-3-FAs ameliorate carbamazepine (CBZ)'s liver-injury, remained unknown. Both FAs significantly-alleviated CBZ-insult; ranked, DHA > EPA, and significantly-suppressed CBZ-elevated markers of liver biochemistry, oxidative-stress, and inflammation. DHA showed no pharmacokinetic-interaction with plasma-CBZ, while EPA raised CBZ-plasma-levels. Histopathologic-analysis confirmed the remedial-DHA/EPA responses.

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Keywords

Carbamazepine
Omega-3-FAs
Cytokines
Oxidative-stress
Clearance
Liver-injury

Abbreviations

CBZ
Carbamazepine
ω-3-FAs
Omega-3-fatty-acids
EPA
Eicosapentaenoic acid
DHA
Docosahexaenoic acid
ALP
Alkaline-phosphatase
γ-GT
Gamma-glutamyl-transferase
TNF-α
Tumor-necrosis-factor-α
CRP
C-reactive-protein
GSH
Reduced-glutathione
MDA
Malondialdehyde

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