Abstract:
Liver toxicity remains a critical barrier in drug development and clinical therapeutics, with
mitochondrial dysfunction (MD) recognized as a central mechanism driving drug-induced liver
injury (DILI). Mitochondrial liabilities contribute substantially to compound attrition, postmarketing
drug withdrawals, and regulatory restrictions. Chloramphenicol, despite its broadspectrum
antimicrobial efficacy, has limited clinical use owing to its mitochondrial toxicity and
associated hepatotoxic effects. In light of these challenges, this research investigates whether
strategic combination therapy specifically with potent antioxidants can mitigate such adverse
effects, potentially rescuing otherwise valuable drugs from late-stage failure or regulatory
rejection. The study evaluates the hepatoprotective potential of two well-characterized
antioxidants, Astaxanthin and Quercetin, against chloramphenicol-induced mitochondrial
toxicity using integrated in-vitro and in-vivo models to elucidate mechanistic pathways and
therapeutic efficacy.In the in-vitro component, HepG2 liver cells were cultured under galactose-adapted conditions
to simulate enhanced mitochondrial reliance. Cells were exposed to chloramphenicol with or
without co-treatment of Astaxanthin or Quercetin. Assays for ATP production, reactive oxygen
species (ROS), and expression of key mitochondrial genes (SOD2, NRF1, SURF1, TFAM, and
UCP2) were performed. Results demonstrated significant ROS attenuation and mitochondrial
gene expression recovery with antioxidant treatment, indicating mitigation of chloramphenicolinduced
toxicity.In the in-vivo arm, male Wistar rats were administered chloramphenicol intraperitoneally,
followed by oral antioxidant therapy. Biochemical markers including glutathione (GSH) and
nitric oxide (NO) were quantified to assess oxidative stress. Both antioxidants significantly
restored GSH levels and reduced NO, with Quercetin showing slightly superior efficacy.
This integrated study demonstrates that both Astaxanthin and Quercetin confer mitochondrial
protection through modulation of oxidative stress and gene expression, suggesting their
therapeutic potential as adjuncts in antibiotic-induced hepatotoxicity. Future investigations
should focus on mechanistic insights, dose optimization, and clinical translation.
