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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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References

  1. Atici S, Cinel I, Cinel L, Doruk N, Eskandari G, Oral U (2005) Liver and kidney toxicity in chronic use of opioids: an experimental long term treatment model. J Biosci 30:245–252

    CAS  PubMed  Google Scholar 

  2. Tolman KG (1998) Hepatotoxicity of non-narcotic analgesics. Am J Med 105:13S-19S

    CAS  PubMed  Google Scholar 

  3. Singhal PC, Sharma P, Sanwal V, Prassad A, Kapasi A, Ranjan R, Franki N, Reddy K, Gibbons N (1998) Morphine modulates proliferation of kidney fibroblasts. Kidney Int 53:350–357

    CAS  PubMed  Google Scholar 

  4. Havig SM, Wiik E, Karinen R, Brochmann GW, Vevelstad M (2016) Codeinespiked beer in a date rape case? Int J Legal Med 130:1513–1518

    PubMed  Google Scholar 

  5. Hudak ML (2016) Codeine pharmacogenetics as a proof of concept for pediatric precision medicine. Pediatrics 138:e20161359. https://doi.org/10.1542/peds.2016-1359

    Article  PubMed  Google Scholar 

  6. International Narcotics Control Board, Narcotic Drugs, Estimated World Requirements for 2012, Statistics for 2010, United Nations, New York, 2012; https://www.incb.org/incb/en/narcotic-drugs/Technical_Reports/2011/narcotic-drugs-technical-report_2011.html. Accessed 2 Aug 2015

  7. Ajayi AF, Akhigbe RE (2020a) Assessment of sexual behaviour and fertility indices in male rabbits following chronic codeine use. Andrology 8:509–515

    CAS  PubMed  Google Scholar 

  8. Akhigbe RE, Ajayi AF (2020) Testicular toxicity following chronic codeine administration is via oxidative DNA damage and up-regulation of NO and caspase 3. PLoS ONE 15(3):e0224052

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Han B, Compton WM, Jones CM, Cai R (2015) Nonmedical prescription opioid use and use disorders among adults aged 18 through 64 years in the United States, 2003–2013. JAMA 314(14):1468–1478

    CAS  PubMed  Google Scholar 

  10. Florence CS, Zhou C, Luo F, Xu L (2016) The economic burden of prescription opioid overdose, abuse, and dependence in the United States, 2013. Med Care 54(10):901–906

    PubMed  Google Scholar 

  11. Rudd RA, Seth P, David F, Scholl L (2016) Increases in drug and opioid-involved overdose deaths—United States, 2010–2015. MMWR Morb Mortal Wkly Rep 65(5051):1445–1452

    PubMed  Google Scholar 

  12. Guy GP Jr, Zhang K, Bohm MK, Losby J, Lewis B, Young R (2017) Vital signs: changes in opioid prescribing in the United States, 2006–2015. MMWR Morb Mortal Wkly Rep 66(26):697–704

    PubMed  PubMed Central  Google Scholar 

  13. Compton WM, Jones CM, Baldwin GT (2016) Relationship between nonmedical prescription-opioid use and heroin use. N Engl J Med 374(2):154–163

    CAS  PubMed  Google Scholar 

  14. Smith HS (2009) Opioid metabolism. Mayo Clin Proc 84(7):613–624

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Smith HS (2011) The metabolism of opioid agents and the clinical impact of their active metabolites. Clin J Pain 27(9):824–838

    PubMed  Google Scholar 

  16. García-Ferreyra J (2015) Sperm DNA fragmentation and its relation with fertility. In: new discoveries in embryology. In Tech Publishers, p 1–17. https://doi.org/10.5772/60825

  17. Kaufmann SH, Hengartner MO (2001) Programmed cell death: alive and well in the new millennium. Trends Cell Biol 11:526–534

    CAS  PubMed  Google Scholar 

  18. Bansal AK, Bilaspuri GS (2011) Impacts of oxidative stress and antioxidants on semen functions. Vet Med Int 9:e686137

    Google Scholar 

  19. Zribi N, Chakroun NF, Elleuch H, Abdallah FB, Ben Hamida AS, Gargouri J, Fakhfakh F, Keskes LA (2011) Sperm DNA fragmentation and oxidation are independent of malondialdheyde. Reprod Biol Endocrinol 9:47

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Cui J, Holmes EH, Greene TG, Liu PK (2000) Oxidative DNA damage precedes DNA fragmentation after experimental stroke in rat brain. FASEB J 14:955–967

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Banks S, King SA, Irvine DS, Saunders PT (2005) Impact of a mild scrotal heat stress on DNA integrity in murine spermatozoa. Reproduction 129:505–514

    CAS  PubMed  Google Scholar 

  22. Ajayi AF, Akhigbe RE (2020b) Codeine induced sperm DNA damage is mediated predominantly by oxidative stress rather than apoptosis. Redox Rep 25(1):33–40

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Salahshoor MR, Abdolmaleki A, Shabanizadeh A, Jalali A, Roshankhah S (2020) Ipomoea aquatica extract reduces hepatotoxicity by antioxidative properties following dichlorvos administration in rats. Chin J Physiol 63:77–84

    PubMed  Google Scholar 

  24. Perandones CE, Illera VA, Peckham D, Stunz LL, Ashman RF (1993) Regulation of apoptosis in vitro in mature murine spleen T cells. J Immunol 151(7):3521–3529

    CAS  PubMed  Google Scholar 

  25. Shigenaga MK, Gimeno CJ, Ames BN (1989) Urinary 8-hydroxy-2_-deoxyguanosine as a biological marker of in vivo oxidative DNA damage. Proc Natl Acad Sci USA 86:9697–9701

    CAS  PubMed  Google Scholar 

  26. Kasai H, Iwamoto-Tanaka N, Miyamoto T, Kawanami K, Kawanami S, Kido R, Ikeda M (2001) Life style and urinary 8-hydroxydeoxygua-nosine, a marker of oxidative DNA damage: effects of exercise, working conditions, meat intake, body mass index, and smoking. Jpn J Cancer Res 92:9–15

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Cooke MS, Lunec J, Evans MD (2002) Progress in the analysis of urinary oxidative DNA damage. Free Radic Biol Med 33:1601–1614

    CAS  PubMed  Google Scholar 

  28. Juel C, Nordsborg NB, Bangsbo J (2013) Exercise-induced increase in maximal in vitro Na, K-TPase activity in human skeletal muscle. Am J Physiol Integr Comp Physiol 304:1161–1165

    Google Scholar 

  29. Saka WA, Akhigbe RE, Ishola OS, Ashamu EA, Olayemi OT, Adeleke GE (2011) Hepatotherapeutic effect of Aloe vera in alcohol-induced hepatic damage. Pak J Biol Sci 14:742–746

    CAS  PubMed  Google Scholar 

  30. Ajayi AF, Akhigbe RE (2012) Implication of altered thyroid state on liver function. Thyroid Res Pract 9:84

    Google Scholar 

  31. Garba US, Sholey ZG, Maryam MB, Usama BU (2017) A survey of the usage and users of codeine containing cough syrups in Maiduguri Nigeria. Adv Psychol Neurosci 2(2–1):42–46

    Google Scholar 

  32. United Nations Office on Drugs and Crime (UNODC). Global overview of drug demand and supply: latest trends, cross-cutting issues. World Drug Report, 2018. Available on https://www.unodc.org/wdr2018

  33. Faden VB, Goldman M (2004/2005) Introduction: alcohol and development in youth—a multidisciplinary overview. Alcohol Res Health 28:107–108

  34. Akhigbe RE (2014) Discordant results in plant toxicity studies in Africa: attempt of standardization. In: Kuete V (ed) Toxicological survey of African medicinal plants, chapter 4. Elsevier, Amsterdam, pp 53–59

    Google Scholar 

  35. Sheweita SA, Almasmari AA, El-Banna SG (2018) Tramadol-induced hepato- and nephrotoxicity in rats: role of curcumin and gallic acid as antioxidants. PLoS ONE 13(8):e0202110

    PubMed  PubMed Central  Google Scholar 

  36. El-Gaafarawi II (2006) Biochemical toxicity induced by tramadol administration in male rats. Egypt J Hospital Med 23:353–362

    CAS  Google Scholar 

  37. Barbosa J, Faria J, Leal S, Afonso L, Lobo J, Queirós O, Moreira R, Carvalho F, Dinis-Oliveira RJ (2017) Acute administration of tramadol and tapentadol at effective analgesic and maximum tolerated doses causes hepato- and nephrotoxic effects in Wistar rats. Toxicology. https://doi.org/10.1016/j.tox.2017.07.001

    Article  PubMed  Google Scholar 

  38. Clausen T, Van Hardeveld C, Everts ME (1991) Significance of cation transport in control of energy metabolism and thermogenesis. Physiol Rev 71:733–774

    CAS  PubMed  Google Scholar 

  39. Therien AG, Goldshleger R, Karlish SJ, Blostein R (1997) Tissue-specific distribution and modulatory role of the gamma subunit of the Na,K-ATPase. J Biol Chem 272:32628–32634

    CAS  PubMed  Google Scholar 

  40. Fuller W, Eaton P, Bell JR (2004) Ischemia-induced phosphorylation of phospholemman directly activates rat cardiac Na/K ATPase. FASEB J 18:197–199

    CAS  PubMed  Google Scholar 

  41. Müller-Ehmsen J, McDonough AA, Farley R (2002) Sodium pump isoform expression in heart failure: implication for treatment. Basic Res Cardiol 97:I25–I30

    PubMed  Google Scholar 

  42. Kelly RA, Balligand JL, Smith TN (1996) Nitric oxide and cardiac function. Circ Res 79:363–380

    CAS  PubMed  Google Scholar 

  43. Davies MG, Fulton GJ, Hagen PO (1995) Clinical biology of nitric oxide. Br J Surg 82:1598–1610

    CAS  PubMed  Google Scholar 

  44. Cook JP, Tsao PS (1993) Cytoprotective effects of nitric oxide. Circulation 88:2451–2454

    Google Scholar 

  45. Beckman JS, Crow JP (1993) Pathological implications of nitric oxide, superoxide and peroxynitrite formation. Biochem Soc Trans 21:330–334

    CAS  PubMed  Google Scholar 

  46. Beckman JS, Beckman TW, Chen J (1990) Apparent hydroxyl radical production of peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 87:1620–1624

    CAS  PubMed  Google Scholar 

  47. Rosselli M, Keller PJ, Dubey RK (1998) Role of nitric oxide in the biology, physiology and pathophysiology of reproduction. Hum Reprod Update 4(1):3–24

    CAS  PubMed  Google Scholar 

  48. Lampiao F, du Plessis SS (2008) TNF-α and IL-6 affect human sperm function by elevating nitric oxide production. Reprod Biomed Online 17(5):628–631

    CAS  PubMed  Google Scholar 

  49. Bonello N, Mckie K, Jasper M (1996) Inhibition of nitric oxide effects on interleukin-1 beta-enhanced ovulation rate, steroid hormone and ovarian leukocyte distribution at ovulation in the rat. Biol Reprod 54:436–445

    CAS  PubMed  Google Scholar 

  50. Porter AG, Janicke RU (1999) Emerging roles of caspase-3 in apoptosis. Cell Death Differ 6:99–104

    CAS  PubMed  Google Scholar 

  51. Sakahira H, Enari M, Nagata S (1998) Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis. Nature 391:96–99

    CAS  PubMed  Google Scholar 

  52. Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Zhang H, Wang L (2002) Theoretical elucidation on structure antioxidant activity relationships for indolinonichydroxylamines. Bioorg Med Chem Lett 12(2):225–227

    CAS  PubMed  Google Scholar 

  54. Susan E (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516

    Google Scholar 

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Authors and Affiliations

  1. Department of Physiology, College of Medicine, Ladoke Akintola University of Technology, Ogbomoso, Oyo, Nigeria

    R. E. Akhigbe & A. F. Ajayi

  2. Department of Biochemistry, Adeleke University, Ede, Osun State, Nigeria

    L. O. Ajayi

  3. Department of Medical Laboratory Science, Babcock University, Ilishan Remo, Ogun State, Nigeria

    A. A. Adelakun

  4. Department of Biochemistry, College of Medicine, Ladoke Akintola University of Technology, Ogbomoso, Oyo, Nigeria

    O. S. Olorunnisola

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  1. R. E. Akhigbe
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  4. O. S. Olorunnisola
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  5. A. F. Ajayi
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Contributions

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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