Multi-drug resistance protein (Mrp) 3 may be involved in resveratrol protection against methotrexate-induced testicular damage

AimsTo investigate the effect of resveratrol (RES) on methotrexate (MTX)-induced testicular damage.Main methodsRES (10 mg/kg/day) was given for 8 days orally and MTX (20 mg/kg i.p.) was given at day 4 of the experiment, with or without RES in rat.Key findingsMTX decreased serum testosterone, induced histopathological testicular damage, and increased testicular tumor necrosis factor-α level and expression of nuclear factor-κB and cyclooxygenase-2. In MTX/RES group, significant reversal of these parameters was noticed, compared to MTX group. Testicular expression of multidrug resistance protein (Mrp) 3 was three- and five-folds higher in RES- and MTX/RES-treated groups, respectively. In vitro, using prostate cancer cells, each of MTX and RES alone induced cytotoxicity with IC50 0.18 ± 0.08 and 20.5 ± 3.6 μM, respectively. RES also significantly enhanced cytotoxicity of MTX.SignificanceThus, RES has dual beneficial effects, as it promotes MTX tumor cytotoxicity, while protecting the testes, probably via up-regulation of testicular Mrp3 as a novel mechanism.