Methotrexate (MTX) is a chemotherapeutic agent used for treating several types of cancer as well as psoriasis and rheumatoid arthritis, but its use is limited due to its nephrotoxicity. The purpose of this research work was to observe ameliorative effects of L‐carnitine (LC) toward renal toxicity caused by MTX and mechanisms responsible for these effects. Thirty‐two male Sprague‐Dawley rats were divided into four groups (eight rats/group), control group (received saline), MTX group (20 mg/kg/i.p. once), LC group (500 mg/kg/i.p. for 5 days), and MTX + LC group (received a single MTX dose 20 mg/kg/i.p. followed by LC 500 mg/kg/i.p. for 5 days). Histopathological examinations, lipid oxidation marker, malondialdehyde (MDA), and the antioxidant superoxide dismutase (SOD) as well as inflammatory (tumor necrosis factor‐α [TNF‐α] and interleukin‐6 [IL‐6]) and apoptotic markers (Bax, Bcl2, and caspase‐3) were used to assess renal toxicity. Moreover, the protein levels of silent information regulator 1 (SIRT1) and its downstream signaling targets, peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α), and nuclear factor erythroid 2‐related factor 2 (Nrf2) in addition to heme oxygenase‐1 (HO‐1) were measured. LC significantly protected against MTX‐induced nephrotoxicity. It ameliorated MTX‐induced renal histopathological changes and diminished MTX‐induced renal oxidative stress, renal inflammation, and apoptosis. LC also upregulated the expression of SIRT1 and PGC‐1 as well as Nrf2 and HO‐1. By controlling the expression of renal SIRT1/PGC‐1/Nrf2/HO‐1, LC displayed antioxidant, anti‐inflammatory, and anti‐apoptotic activities. Hence, using LC supplements may help prevent negative MTX side effects.

Introduction and aim: An accidental or intentional paracetamol overdosage is a common condition, with hepatic injury as a common complication. Kidney could be injured in association with hepatic injury. Prevention and/or proper treatment is markedly important. The current study aimed to investigate the role of vitamin D (VD) in acute paracetamol-induced hepatorenal damage. Methodology: Fourty male Wister rats were divided into 4 equal groups. The negative control (NC), the positive control (PC) (received paracetamol 1200mg/kg), prophylactic group (received VD (1000 IU/Kg/day) before induction of toxicity and treatment continued after induction); and the treatment group with VD (2000 IU/Kg/day) for five successive days after induction of toxicity, for three successive cycles. VD levels, serum liver enzymes, total protein, albumin, serum urea and creatinine were estimated. The concentrations of interferon-γ (IFN- γ), interleukins (IL1β, IL4, IL10, and IL-17) in the tissue lysate were determined. The oxidative stress indicators and antioxidant enzymes (glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), glutathione (GSH) and Malonaldehyde (MDA)) were also measured. Results: Liver enzymes, serum urea and creatinine were increased in PC than NC groups, and were significantly reduced in prophylactic and treatment groups. But not return normal values, and prophylactic group is better. Total proteins and albumin significantly reduced by paracetamol toxicity and returned to near normal with VD supplementation.  Vitamin-D levels were significantly reduced in PC than NC groups. However, it was significantly increased in prophylactic and treatment groups than NC and PC groups. IFN- γ, IL-1β, IL-17, and MDA were significantly increased, while IL-10, GPx, CAT, and GSH were significantly reduced in PC than NC groups. Prophylactic and treatment groups improved the values. However, SOD significantly reduced in PC than NC group. Vitamin D was significantly and inversely correlated with ALT, AST, ALP, albumin, creatinine, liver and kidney IFN-γ, IL-1β, IL-17 and MDA. But, it was proportionately and significantly correlated with liver and kidney IL-10. Conclusion: Acute paracetamol toxicity alters hepatic and renal VD homeostasis through oxidative stress and pro-inflammation. Vitamin D supplementation had an ameliorative action on hepatorenal injury, and the long duration of VD supplementation had better outcome.