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Codeine-induced hepatic injury is via oxido-inflammatory damage and caspase-3-mediated apoptosis

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Abstract

Codeine (3-methylmorphine) is a known analgesic, antitussive, and antidiarrheal drug that is often abused for recreational purposes. It is metabolized in the liver via the cytochrome P450 system and thus hypothesized to induce hepatic injury especially when misused. Thus, the present study aimed at investigating changes in liver function, hepatic enzyme biomarker, proton pumps, antioxidant status, free radicals and TNF-α levels, as well as caspase 3 activities and hepatic DNA fragmentation after 6 weeks of oral codeine administration. Twenty-one male rabbits were randomized into 3 groups (n = 7). The control group had 1 ml of normal saline, while the low-dose and high-dose codeine groups received 4 and 10 mg/kg b.w of codeine respectively daily. The codeine-treated animals had significantly lower levels of serum proteins, increased activities of hepatic enzyme biomarkers and caspase 3, raised hepatic concentrations of free radicals and TNF-α, as well as increased hepatic DNA fragmentation. Codeine treatment also led to a significant decline in hepatic weight, activities of hepatic enzymatic antioxidant, Na+-K+-ATPase and Ca2+-ATPase. These alterations were more pronounced in high-dose codeine treated animals than in the low-dose group. Histopathological study showed moderate fatty degeneration of hepatic parenchyma, infiltration of the portal tract by inflammatory cells with dense collagen fibre deposition in codeine-treated animals. The present study revealed that codeine induced liver injury and hepatic DNA damage via caspase 3-dependent signaling by suppressing hepatic antioxidant status and enhancing free radical and TNF-α generation.

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ARE and AAF conceived the study. ARE, OOS, and AAF designed the study. ARE, ALO, and AAA carried out the study. Statistical analysis was done by ARE, ALO, and AAF. OOS and AAF supervised the study. The first draft was written by ARE and revised by ALO, AAA, OOS, and AAF. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

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Correspondence to A. F. Ajayi.

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The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

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Akhigbe, R.E., Ajayi, L.O., Adelakun, A.A. et al. Codeine-induced hepatic injury is via oxido-inflammatory damage and caspase-3-mediated apoptosis. Mol Biol Rep 47, 9521–9530 (2020). https://doi.org/10.1007/s11033-020-05983-6

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