Indication of doxorubicin cardiotoxicity by impairment of 131I-pIPPA utilization

Abstract

The present study was designed to evaluate if doxorubicin (D) can impair myocardial fatty acid utilization. To this end we studied the myocardial utilization of 131I-pIPPA in untreated (Co, n=6) and D (20 mg/kg intraperitoneal) treated rats. D was given 24 h (24 D, n=6) and 48 hours (48 D, n=6) before tracer administration. One min after i.v. 131I-pIPPA (50 μCi) injection, the hearts were rapidly removed, frozen in liquid nitrogen, weighed, and counted. Following lipid extraction of homogenized heart extracts 131 I radioactivity distribution was analyzed by thin-layer chromatography (TLC). In additional rat experiments, high energy phosphates (12 rats/group) and carnitine (20 rats/group) were determined enzymatically in heart extracts. The mean pIPPA uptake in rat heart (%dose/g) was 2.49 in Co, 1.74 in 24 D, and 2.36 in 48 D rats. Usually five peaks were separated by TLC, that with a mean Rf value of 0.92 corresponding to 131I-pIPPA, the remaining four representing catabolites of pIPPA metabolism. The mean relative amount of unmetabolized 131I-pIPPA as compared to the sum of 131I-pIPPA catabolites was less in Co than in 24 D or 48 D rats (P<0.05) (\(\bar x\): 46.5% vs 72.4% vs 59.4%, respectively). The mean carnitine content of heart extracts was higher in Co (0.55 μM/g) than in D treated rats (24 D, 0.42 μM/g; 48 D, 0.46 μM/g) P<0.05). The total amount of higher energy phosphates was not different between the groups. However the mean ATP/AMP ratio was higher in Co (35.9) than in 24 D (22.3) or 48 D (27.1) rats (P<0.05). We conclude that D therapy is accompanied by a partial reversible impairment in myocardial pIPPA utilization, possibly mediated by carnitine deficiency. Thus, 131I-pIPPA might be useful in patients on D therapy to evaluate eventual D-induced effects on myocardial fatty acid utilization.