title: Effect of protein malnutrition on the metabolism and toxicity of cisplatin, 5-fluorouracil and mitomycin C in rat stomach.
abstract: This study investigated the effect of protein malnutrition on metabolism and toxicity of cisplatin (CP), 5-fluorouracil (FU) and mitomycin C (MMC) in rat stomach. Weanling male Wistar rats received a normal (24%) or low (2.5%) protein diet for 28 days and were allocated into: normally-fed control, protein-malnourished control (PM), 3 normally-fed drug-treated groups and 3 protein-malnourished drug-treated groups (PM-CP, PM-FU and PM-MMC). Cisplatin and MMC were injected intraperitoneally (8 mg/kg on day 26 and 1 mg/kg/day for 7 days, respectively). 5-Fluorouracil was given orally (50 mg/kg/day for 5 days). Compared with normally-fed counterparts, PM-CP rats exhibited higher glutathione S-transferase, aminopeptidase N and cysteine S-conjugate beta-lyase (CCBL) and lower gamma-glutamyltransferase activities, PM-FU rats exhibited decreased dihydropyrimidine dehydrogenase and cytochrome P450 1A1/2 activities and PM-MMC rats showed higher quinone reductase and depleted xanthine oxidase activities. Protein-malnourished drug-treated groups exhibited exacerbated gastrotoxicity, relative to normally-fed counterparts, manifested by lower mucus levels, higher permeability and histopathological deterioration, along with increased oxidative stress in PM-CP rats and exaggerated prostaglandin E2 production in PM-MMC rats. Conclusively, protein malnutrition alters CP, FU and MMC metabolism in rat stomach by enhancing CCBL pathway for CP activation, delaying FU elimination and activating two-electron reduction of MMC, potentiating their gastrotoxicity.
authors: Biochemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Eini Street, Cairo 11562, Egypt.
authors: Tarek K
authors: TK
authors: Motawi
authors: Hanan M
authors: HM
authors: Abd-Elgawad
authors: Nancy N
authors: NN
authors: Shahin
mesh_terms: D000818:Animals; D013437:Carbon-Sulfur Lyases / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism; D005472:Fluorouracil / Q000008:administration & dosage / Q000633:toxicity*; D005753:Gastric Mucosa / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D008297:Male; D016685:Mitomycin / Q000008:administration & dosage / Q000633:toxicity*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D011502:Protein-Energy Malnutrition / Q000139:chemically induced / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D013270:Stomach / Q000187:drug effects*; D014969:Xanthine Oxidase / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000378:metabolism
chemical_list: D016685:Mitomycin; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D014969:Xanthine Oxidase; D042943:Dihydrouracil Dehydrogenase (NADP); D016660:NAD(P)H Dehydrogenase (Quinone); D005723:gamma-Glutamyltransferase; D005982:Glutathione Transferase; D013437:Carbon-Sulfur Lyases; C108902:cysteine-S-conjugate beta-lyase; D002945:Cisplatin; D005472:Fluorouracil