Codeine-induced hepatic injury is via oxido-inflammatory damage and caspase-3-mediated apoptosis
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ORIGINAL ARTICLE
Codeine‑induced hepatic injury is via oxido‑inflammatory damage and caspase‑3‑mediated apoptosis R. E. Akhigbe1 · L. O. Ajayi2 · A. A. Adelakun3 · O. S. Olorunnisola4 · A. F. Ajayi1 Received: 13 July 2020 / Accepted: 5 November 2020 © Springer Nature B.V. 2020
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. Keywords Codeine · 3-Methylmorphine · Hepatic DNA damage · DNA fragmentation · Oxidative stress · Inflammation
Introduction Drug-induced hepatic injury is a global phenomenon. This is due to the central role of the liver in drug metabolism [1]. The liver converts drugs and other xenobiotics into their metabolites which are readily excreted [2]. Although the metabolites may be more biologically active than the drug, either may cause cellular damage to the liver [3]. * A. F. Ajayi [email protected] 1
Department of Physiology, College of Medicine, Ladoke Akintola University of Technology, Ogbomoso, Oyo, Nigeria
2
Department of Biochemistry, Adeleke University, Ede, Osun State, Nigeria
3
Department of Medical Laboratory Science, Babcock University, Ilishan Remo, Ogun State, Nigeria
4
Department of Biochemistry, College of Medicine, Ladoke Akintola University of Technology, Ogbomoso, Oyo, Nigeria
Codeine, also known as 3-methylmorphine, is an opioid that is commonly used as an analgesic [4], antitussive, and anti-motility drug [5]. As with other opiates, the misuse/ abuse of co
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