title: Protective mechanisms of resveratrol against methotrexate-induced renal damage may involve BCRP/ABCG2.
abstract: Resveratrol (RES) is a well-known polyphenol antioxidant. We have previously shown that testicular protective effect of RES against the anticancer drug methotrexate (MTX)-induced toxicity involves transporter-mediated mechanisms. Here, we investigated the effect of RES on MTX-induced nephrotoxicity. Rats were administered RES (10 mg/kg/day) for 8 days, with or without a single MTX dose (20 mg/kg i.p.) at day 4 of the experiment. MTX induced nephrotoxicity, as evidenced by a significant increase in serum blood urea nitrogen and creatinine compared to the control, as well as distortion of kidney microscopic structure. MTX also significantly increased renal nitric oxide level along with inducible nitric oxide synthase, fas ligand, and caspase 3 expressions. Administering RES prior to MTX significantly improved kidney function and microscopic picture and also significantly decreased nitrosative and apoptotic markers compared to MTX alone. RES, but not MTX, caused a significant increase in expression of breast cancer resistance protein (BCRP), an apical efflux renal transporter that participates in urinary elimination of both MTX and RES. Interestingly, concomitant MTX and RES caused further upregulation of renal BCRP compared to RES alone. Using Human BCRP ATPase assay, both RES and MTX exhibited a dose-dependent increase in ATPase activity, with Km values of 0.52 ± 0.03 and 30.9 ± 4.2 μm, respectively. Furthermore, combined RES and MTX caused ATPase activity which was significantly less than maximum ATPase activity attained by the positive control, sulfasalazine (12.5 μm). In conclusion, RES exerted nephroprotection against MTX-induced toxicity through antinitrosative and anti-apoptotic effects, as well as via upregulation of renal BCRP.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia, 61511, Egypt.
authors.forename: Azza A K
authors.initials: AA
authors.lastname: El-Sheikh
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia, 61511, Egypt. momorsy@kfu.edu.sa.|Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, 31982, Saudi Arabia. momorsy@kfu.edu.sa.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Morsy
authors.affiliation: Department of Physiology, Biochemistry and Pharmacology, College of Veterinary Medicine, King Faisal University, Al-Ahsa, 31982, Saudi Arabia.
authors.forename: Abdulla Y
authors.initials: AY
authors.lastname: Al-Taher
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000096:biosynthesis*; D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity; D000975:Antioxidants / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000633:toxicity*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D020011:Protective Agents / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D000077185:Resveratrol; D013267:Stilbenes / Q000627:therapeutic use*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000964:Antimetabolites, Antineoplastic; D000975:Antioxidants; D009363:Neoplasm Proteins; D020011:Protective Agents; D013267:Stilbenes; D000077185:Resveratrol; D008727:Methotrexate
keywords: breast cancer resistance protein; caspase 3; inducible nitric oxide synthase; methotrexate; nephrotoxicity; resveratrol