Codeine exerts cardiorenal injury via upregulation of adenine deaminase/xanthine oxidase and caspase 3 signaling

Life Sci. 2021 May 15:273:118717. doi: 10.1016/j.lfs.2020.118717. Epub 2020 Nov 4.


Aims: Codeine treatment has been shown to be associated with glucolipid deregulation, though data reporting this are inconsistent and the mechanisms are not well understood. Perturbation of glutathione-dependent antioxidant defense and adenosine deaminase (ADA)/xanthine oxidase (XO) signaling has been implicated in the pathogenesis of cardiometabolic disorders. We thus, hypothesized that depletion of glutathione contents and upregulation of ADA/XO are involved in codeine-induced glucolipid deregulation. The present study also investigated whether or not codeine administration would induce genotoxicity and apoptosis in cardiac and renal tissues.

Materials and methods: Male New Zealand rabbits received per os distilled water or codeine, either in low dose (4 mg/kg) or high dose (10 mg/kg) for 6 weeks.

Key findings: Codeine treatment led to reduced absolute and relative cardiac and renal mass independent of body weight change, increased blood glucose, total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL-C), as well as increased atherogenic indices and triglyceride-glucose index (TyG). Codeine administration significantly increased markers of cardiac and renal injury, as well as impaired cardiorenal functions. Codeine treatment also resulted in increased cardiac and renal malondialdehyde, Advanced Glycation Endproducts (AGE) and 8-hydroxydeoxyguanosine (8-OH-dG), and myeloperoxidase (MPO), ADA, XO, and caspase 3 activities. These observations were accompanied by impaired activities of cardiac and renal proton pumps.

Significance: Findings of this study demonstrate that upregulation of ADA/XO and caspase 3 signaling are, at least partly, contributory to the glucolipid deregulation and cardiorenal injury induced by codeine.

Keywords: 3-Methylmorphine; Adenosine deaminase; Cardiometabolic disorder; Cardiorenal dysmetabolism; Genotoxicity; Xanthine oxidase.

MeSH terms

  • Acute Kidney Injury / chemically induced
  • Acute Kidney Injury / metabolism
  • Acute Kidney Injury / pathology*
  • Adenosine Deaminase / metabolism*
  • Animals
  • Apoptosis
  • Caspase 3 / metabolism*
  • Codeine / toxicity*
  • Gene Expression
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Glucose / metabolism
  • Heart / drug effects
  • Heart / physiopathology*
  • Insulin Resistance
  • Male
  • Narcotics / toxicity
  • Rabbits
  • Triglycerides / metabolism
  • Up-Regulation
  • Xanthine Oxidase / metabolism*


  • Narcotics
  • Triglycerides
  • Xanthine Oxidase
  • Caspase 3
  • Adenosine Deaminase
  • Glucose
  • Codeine