A C-13 NMR-STUDY OF 2-C-13-CHLOROACETALDEHYDE, A METABOLITE OF IFOSFAMIDE AND CYCLOPHOSPHAMIDE, IN THE ISOLATED-PERFUSED RABBIT HEART MODEL- INITIAL OBSERVATIONS ON ITS CARDIOTOXICITY AND CARDIAC METABOLISM
C. Joqueviel et al., A C-13 NMR-STUDY OF 2-C-13-CHLOROACETALDEHYDE, A METABOLITE OF IFOSFAMIDE AND CYCLOPHOSPHAMIDE, IN THE ISOLATED-PERFUSED RABBIT HEART MODEL- INITIAL OBSERVATIONS ON ITS CARDIOTOXICITY AND CARDIAC METABOLISM, Cellular and molecular biology, 43(5), 1997, pp. 773-782
The metabolism of 2-C-13-chloroacetaldehyde at doses of 1.5, 2, 3 and
4 mg/kg b.w. and that of 2-C-13-chloroacetate at a dose of 5.9 mg/kg b
.w. were studied in the isolated perfused rabbit heart model using car
bon-13 nuclear magnetic resonance. We have shown that, whereas chloroa
cetaldehyde is cardiotoxic at doses above 2 mg/kg b.w., this toxic eff
ect is not accompanied by an increase in intramyocardial citrate level
s. Chloroacetate, its main metabolite, is not cardiotoxic. The metabol
ism of chloroacetaldehyde is complex and leads, in addition to chloroa
cetate, to chloroethanol, glycolic acid, conjugates of glutathione wit
h chloroacetate or chloroethanol (and/or their metabolites, S-(2-carbo
xymethyl) cysteine, N-acetyl-S-(2-carboxymethyl) cysteine, S-(2-hydrox
yethyl) cysteine) and thiodiglycolic acid. Low amounts of chloroacetat
e are metabolized by isolated perfused rabbit hearts into glycolic aci
d and glutathione conjugate (and/or its metabolites, S-(2-carboxymethy
l) cysteine, N-acetyl-S-(2-carboxymethyl) cysteine). The present resul
ts suggest the need to evaluate further the role that chloroacetaldehy
de may play in the cardiotoxic effects of ifosfamide and cyclophospham
ide.