title: In vitro effects of platinum compounds on renal cellular respiration in mice.
abstract: BACKGROUND
  Cisplatin, carboplatin and oxaliplatin are structurally-related compounds, which are commonly used in cancer therapy. Cisplatin (Platinol(®)) has Boxed Warning stating: "Cumulative renal toxicity associated with PLATINOL is severe", while carboplatin and oxaliplatin are less nephrotoxic. These drugs form platinum adducts with cellular DNA. Their bindings to cellular thiols (e.g., glutathione and metallothionein) are known to contribute to drug resistance while thiol depletion augments platinum toxicity.
  
  
  METHODS
  Using phosphorescence oxygen analyzer, this study investigated the effects of platinum drugs on renal cellular respiration (mitochondrial O2 consumption) in the presence and absence of the thiol blocking agent N-ethylmaleimide (used here as a model for thiol depletion). Renal cellular ATP was also determined. Kidney fragments from C57BL/6 mice were incubated at 37 °C in Krebs-Henseleit buffer (gassed with 95% O2:5% CO2) with and without 100 μM platinum drug in the presence and absence of 100 μM N-ethylmaleimide for ≤ 6 h.
  
  
  RESULTS
  Platinum drugs alone had no effects on cellular respiration (P ≥ 0.143) or ATP (P ≥ 0.161). N-ethylmaleimide lowered cellular respiration (P ≤ 0.114) and ATP (P = 0.008). The combination of platinum drug and N-ethylmaleimide significantly lowered both cellular respiration (P ≤ 0.006) and ATP (P ≤ 0.003). Incubations with N-ethylmaleimide alone were associated with moderate-to-severe tubular necrosis. Incubations with cisplatin+N-ethylmaleimide vs. cisplatin alone produced similar severities of tubular necrosis. Tubular derangements were more prominent in carboplatin+N-ethylmaleimide vs. carboplatin alone and in oxaliplatin+N-ethylmaleimide vs. oxaliplatin alone.
  
  
  CONCLUSIONS
  These results demonstrate the adverse events of thiol depletion on platinum-induced nephrotoxicities. The results suggest cellular bioenergetics is a useful surrogate biomarker for assessing drug-induced nephrotoxicities.
authors.affiliation: Department of Pathology, College of Medicine and Health Sciences, U.A.E. University P.O. Box: 17666, Al-Ain, Abu Dhabi, United Arab Emirates.
authors.forename: Saeeda-S
authors.initials: SS
authors.lastname: Almarzooqi
authors.affiliation: Department of Internal Medicine, College of Medicine and Health Sciences, U.A.E. University P.O. Box: 17666, Al-Ain, Abu Dhabi, United Arab Emirates.
authors.forename: Ali-S
authors.initials: AS
authors.lastname: Alfazari
authors.affiliation: Department of Internal Medicine, College of Medicine and Health Sciences, U.A.E. University P.O. Box: 17666, Al-Ain, Abu Dhabi, United Arab Emirates.
authors.forename: Hidaya-M
authors.initials: HM
authors.lastname: Abdul-Kader
authors.affiliation: Department of Pathology, College of Medicine and Health Sciences, U.A.E. University P.O. Box: 17666, Al-Ain, Abu Dhabi, United Arab Emirates.
authors.forename: Dhanya
authors.initials: D
authors.lastname: Saraswathiamma
authors.affiliation: Department of Pathology, College of Medicine and Health Sciences, U.A.E. University P.O. Box: 17666, Al-Ain, Abu Dhabi, United Arab Emirates.
authors.forename: Alia-S
authors.initials: AS
authors.lastname: Albawardi
authors.affiliation: Department of Pediatrics, College of Medicine and Health Sciences, U.A.E. University P.O. Box: 17666, Al-Ain, Abu Dhabi, United Arab Emirates.
authors.forename: Abdul-Kader
authors.initials: AK
authors.lastname: Souid
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D019069:Cell Respiration / Q000187:drug effects*; D005033:Ethylmaleimide / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D017671:Platinum Compounds / Q000633:toxicity*; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013439:Sulfhydryl Reagents / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D017671:Platinum Compounds; D013438:Sulfhydryl Compounds; D013439:Sulfhydryl Reagents; D005033:Ethylmaleimide
keywords: Mitochondria; O2 consumption; carboplatin; cellular respiration; cisplatin; oxaliplatin; renal tissue