title: 5-Aminolevulinic acid protects against cisplatin-induced nephrotoxicity without compromising the anticancer efficiency of cisplatin in rats in vitro and in vivo.
abstract: OBJECTIVE
  Nephrotoxicity is a frequent and major limitation in cisplatin (CDDP)-based chemotherapy. 5-Aminolevulinic acid (ALA) is widely distributed in animal cells, and it is a precursor of tetrapyrole compounds such as heme that is fundamentally important in aerobic energy metabolism. The aim of this study is to evaluate the protective role of ALA in CDDP-induced acute kidney injury (AKI).
  
  
  METHODS
  We used CDDP-induced AKI rat model and cultured renal tubular cells (NRK-52E). We divided four groups of rats: control, CDDP only, CDDP + ALA(post);(ALA 10 mg/kg + Fe in drinking water) after CDDP, CDDP + ALA(pre & post).
  
  
  RESULTS
  CDDP increased Cr up to 6.5 mg/dl, BUN up to 230 mg/dl, and ALA significantly reduced these changes. ALA ameliorates CDDP-induced morphological renal damages, and reduced tubular apoptosis evaluated by TUNEL staining and cleaved caspase 3. Protein and mRNA levels of ATP5α, complex(COX) IV, UCP2, PGC-1α in renal tissue were significantly decreased by CDDP, and ALA ameliorates reduction of these enzymes. In contrast, Heme Oxigenase (HO)-1 level is induced by CDDP treatment, and ALA treatment further up-regulates HO-1 levels. In NRK-52E cells, the CDDP-induced reduction of protein and mRNA levels of mitochondrial enzymes was significantly recovered by ALA + Fe. CDDP-induced apoptosis were ameliorated by ALA + Fe treatment. Furthermore, we evaluated the size of transplantated bladder carcinoma to the rat skin, and ALA did not change the anti cancer effects of CDDP.
  
  
  CONCLUSIONS
  These data suggested that the protective role of ALA in cisplatin-induced AKI is via protection of mitochondrial viability and prevents tubular apoptosis. Also there are no significant effects of ALA on anticancer efficiency of CDDP in rats. Thus, ALA has the potential to prevent CDDP nephrotoxicity without compromising its anticancer efficacy.
authors: Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Japan.
authors: Yoshio
authors: Y
authors: Terada
authors: Keiji
authors: K
authors: Inoue
authors: Tatsuki
authors: T
authors: Matsumoto
authors: Masayuki
authors: M
authors: Ishihara
authors: Kazu
authors: K
authors: Hamada
authors: Yoshiko
authors: Y
authors: Shimamura
authors: Koji
authors: K
authors: Ogata
authors: Kosuke
authors: K
authors: Inoue
authors: Yoshinori
authors: Y
authors: Taniguchi
authors: Taro
authors: T
authors: Horino
authors: Takashi
authors: T
authors: Karashima
authors: Kenji
authors: K
authors: Tamura
authors: Hideo
authors: H
authors: Fukuhara
authors: Shimpei
authors: S
authors: Fujimoto
authors: Masayuki
authors: M
authors: Tsuda
authors: Taro
authors: T
authors: Shuin
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000622:Aminolevulinic Acid / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002945:Cisplatin / Q000009:adverse effects*; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000494:pharmacology; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D010086:Oxidative Phosphorylation Coupling Factors / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020011:Protective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin; D046509:Tissue Culture Techniques; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D000071246:Uncoupling Protein 2; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D007473:Ion Channels; D024101:Mitochondrial Proteins; D010086:Oxidative Phosphorylation Coupling Factors; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D020011:Protective Agents; D014157:Transcription Factors; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; D000622:Aminolevulinic Acid; D007501:Iron; D051547:Heme Oxygenase-1; D003576:Electron Transport Complex IV; D053148:Caspase 3; C000628217:F(6) ATPase; D025261:Mitochondrial Proton-Translocating ATPases; D002945:Cisplatin