Toxicity of chloroacetaldehyde is similar in adult and pediatric kidney tubules.
The nephrotoxicity of chloroacetaldehyde (CAA), one of the main products of hepatic ifosfamide metabolism, was compared in isolated human pediatric and adult renal tubules. Tubules metabolizing lactate were incubated in the presence of various concentrations of CAA (0.1-0.5 mM). Both at low, clinically relevant (0.2 mM), and at higher concentrations (0.3, 0.4 and 0.5 mM), CAA induced a cellular depletion of thiol compounds, i.e. glutathione, coenzyme A and acetyl-coenzyme A that are involved in CAA detoxication and cellular energy metabolism, respectively. The toxicity to renal cells was clearly observed in the presence of 0.4 and 0.5 mM CAA, which led to a fall of the cellular ATP level, to the accumulation of pyruvate and the inhibition of glucose synthesis from lactate. Inhibition of lactate uptake and an increase in the release of lactate dehydrogenase were observed only in the presence of 0.5 mM CAA. The sensitivity of pediatric tubules to the toxic effects of CAA and the rate of their CAA uptake were not statistically different from those found in adult tubules. It is concluded that an increased susceptibility of pediatric tubules to CAA toxicity cannot be put forward to explain the increased risk for ifosfamide-induced nephrotoxicity in children relative to adults.
Dubourg
Laurence
L
Laboratoire de Physiopathologie Métabolique et Rénale, INSERM Unité N 499, Faculté de Médecine R.T.H. Laennec, 12 rue G. Paradin, 69372 Lyon Cedex 08, France.
Tanière
Philippe
P
Cochat
Pierre
P
Baverel
Gabriel
G
Michoudet
Christian
C
D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000506:poisoning*; D000368:Aged; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D019344:Lactic Acid / Q000378:metabolism; D009994:Osmolar Concentration; D013438:Sulfhydryl Compounds / Q000378:metabolism
D013438:Sulfhydryl Compounds; D019344:Lactic Acid; C004656:chloroacetaldehyde; D000079:Acetaldehyde