A 13C NMR study of 2-(13)C-chloroacetaldehyde, a metabolite of ifosfamide and cyclophosphamide, in the isolated perfused rabbit heart model. Initial observations on its cardiotoxicity and cardiac metabolism.
The metabolism of 2-(13)C-chloroacetaldehyde at doses of 1.5, 2, 3 and 4 mg/kg b.w. and that of 2-(13)C-chloroacetaldehyde at a dose of 5.9 mg/kg b.w. were studied in the isolated perfused rabbit heart model using carbon-13 nuclear magnetic resonance. We have shown that, whereas chloroacetaldehyde is cardiotoxic at doses above 2 mg/kg b.w., this toxic effect is not accompanied by an increase in intramyocardial citrate levels. Chloroacetate, its main metabolite, is not cardiotoxic. The metabolism of chloroacetaldehyde is complex and leads, in addition to chloroethanol, glycolic acid, conjugates of glutathione with chloroacetate or chloroethanol (and/or their metabolites, S-(2-carboxymethyl) cysteine, N-acetyl-S-(2-carboxymethyl) cysteine, S-(2-hydroxymethyl)cysteine) and thiodiglycolic acid. Low amounts of chloroacetate are metabolized by isolated perfused rabbit hearts into glycolic acid and glutathione conjugate (and/or its metabolites, S-(2-carboxymethyl) cysteine, N-acetyl-S-(2-carboxymethyl)cysteine). The present results suggest the need to evaluate further the role that chloroacetaldehyde may play in the cardiotoxic effects of ifosfamide and cyclophosphamide.
Loqueviel
C
C
IMRCP Laboratory, Université Paul Sabatier, Toulouse, France.
Malet-Martino
M
M
Martino
R
R
D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000085:Acetates / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002247:Carbon Isotopes; D003520:Cyclophosphamide / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006016:Glycolates / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D007069:Ifosfamide / Q000378:metabolism*; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010477:Perfusion; D011817:Rabbits
D000085:Acetates; D002247:Carbon Isotopes; D006016:Glycolates; C031149:glycolic acid; C006972:chloroacetic acid; D003520:Cyclophosphamide; C004656:chloroacetaldehyde; D005978:Glutathione; D000079:Acetaldehyde; D007069:Ifosfamide