Testicular toxicity following chronic codeine administration is via oxidative DNA damage and up-regulation of NO and caspase 3

Abstract

Background: Codeine, a 3-methylmorphine, and other related opioids have been implicated in androgen suppression, although the associated mechanisms remain unclear.Aim: Therefore, the objective of the current study was to elucidate the in vivo molecular mechanisms underlying codeine-induced androgen suppression.Methods: This study made use of Twenty-one healthy male rabbits, distributed into three groups randomly, control and codeine-treated groups. The control had 1ml of normal saline daily p.o.The codeine-treated groups received either 4mg/kg b.w of codeine or 10mg/kg b.w of codeine p.o. for six weeks. Reproductive hormonal profile, testicular weight, enzymes, oxidative and inflammatory parameters, histological examination and apoptosis marker were evaluated to examine the effects of codeine use.Key findings: Oral administration of codeine resulted in testicular atrophy and alterations in testicular histomorphology, elevated testicular enzymes, and suppression of circulatory and intratesticular testosterone. These changes were associated with a marked rise in oxidative markers, including oxidative DNA damage, inflammatory response, and caspase-dependent apoptosis.Significance: In conclusion, chronic codeine use resulted in testicular degeneration and testosterone suppression, which may be attributable to nitric oxide-/oxidativestress-mediated caspase-dependent apoptotic testicular cell death.

Apoptotic inducement of neuronal cells by codeine: possible role of disrupted redox state and caspase 3 signaling

“…Hence, 8-OHdG is an established biomarker of oxidative DNA damage (genotoxicity). The observed increase in 8OHdG in the brain following codeine administration corroborates our previous findings that demonstrated the potential of codeine to stimulate oxidative DNA damage of the testis [13,14], sperm [15], liver [16], heart [17], and kidney [17].…”

“…The control group received distilled water (vehicle; p.o ) daily. The low-dose codeine-treated group was administered ( po ) 4 mg/kg/day codeine, while the high-dose codeine-treated group had 10 mg/kg/day codeine po for six weeks [ 10 , 13 , 14 , 15 , 16 , 17 ]. Treatments were discontinued at least 24 h before the termination of the study.…”

“…Markers of oxidative stress, neutrophil inflammation, and enzymatic antioxidants were assayed using standardized enzymatic colorimetric method with assay kit as previously documented in our studies [ 13 , 27 , 28 , 29 , 30 ]. Briefly, MDA, the marker of lipid peroxidation, was measured as the amount of thiobarbituric acid reactive substance, TBARS, generated during lipid peroxidation.…”

“…This method is based on the reaction between 2- thiobarbituric acid (TBA) and malondialdehyde, an end product of lipid peroxidation. On heating in acidic pH, a pink chromogen complex ([TBS] 2-malondialdehyde adduct) is formed and measured by its absorbance at 532 [ 13 , 30 ].…”

“…Although its therapeutic values for pain, cough, Restless Leg Syndrome, and persistence cannot be undermined, its addictive potential puts it at risk of abuse. Though previous studies have documented its potential to enhance copulatory locomotion [ 10 ], it reduces fertility indices [ 10 ], causes testicular toxicity [ 13 , 14 ], and low sperm quality [ 14 , 15 ] via stimulation of oxidative stress, inflammation, and apoptosis. Further studies demonstrated that codeine induced hepatic [ 16 ] and cardiorenal damage [ 17 ] via caspase 3-dependent apoptosis.…”