Kashfi K, Israel M, Sweatman T W, Seshadri R, Cook G A
Department of Pharmacology, College of Medicine, University of Tennessee, Memphis 38163.
Biochem Pharmacol. 1990 Oct 1;40(7):1441-8. doi: 10.1016/0006-2952(90)90438-q.
Adriamycin (ADR; doxorubicin) and its highly lipophilic, less toxic analogue N-benzyl-adriamycin-14-valerate (AD 198) were found to inhibit rat heart and liver carnitine palmitoyltransferases of both mitochondrial outer and inner membranes. The outer membrane enzyme was more sensitive to inhibition by these drugs than the inner membrane enzyme, and AD 198 was a more potent inhibitor of these enzymes than ADR. Other analogues of ADR, N-trifluoroacetyladriamycin-14-valerate (AD 32) and N-trifluoroacetyladriamycin-14-O-hemiadipate (AD 143), which are documented as being noncardiotoxic, were also more potent inhibitors of the mitochondrial carnitine palmitoyltransferases than ADR. Overall, the cardiac mitochondrial carnitine palmitoyltransferases seemed to be slightly more sensitive to the inhibitory effects of ADR and its analogues than the liver enzyme. ADR was an uncompetitive inhibitor with respect to palmitoyl-CoA and a noncompetitive inhibitor with respect to carnitine for both mitochondrial outer and inner membrane enzymes. Our data suggest that mitochondria can take up ADR and concentrate it within the matrix, as is known to happen with other positively-charged compounds. More ADR was found associated with the mitochondrial inner membrane than with the outer membrane; this could be due to the greater protein content of the inner membrane rather than drug binding to cardiolipin. Although inhibition of cardiac inner membrane carnitine palmitoyltransferase has been implicated previously as part of the cardiotoxicity mechanism of ADR, the present findings with ADR and its noncardiotoxic analogues do not support this view.
阿霉素（ADR；多柔比星）及其亲脂性高、毒性较低的类似物N-苄基阿霉素-14-戊酸酯（AD 198）被发现可抑制大鼠心脏和肝脏线粒体外膜和内膜的肉碱棕榈酰转移酶。外膜酶比内膜酶对这些药物的抑制作用更敏感，且AD 198对这些酶的抑制作用比阿霉素更强。阿霉素的其他类似物，N-三氟乙酰阿霉素-14-戊酸酯（AD 32）和N-三氟乙酰阿霉素-14-O-半己二酸酯（AD 143），已被证明无心脏毒性，它们对线粒体肉碱棕榈酰转移酶的抑制作用也比阿霉素更强。总体而言，心脏线粒体肉碱棕榈酰转移酶似乎比肝脏酶对阿霉素及其类似物的抑制作用稍更敏感。对于线粒体外膜和内膜酶，阿霉素对棕榈酰辅酶A是反竞争性抑制剂，对肉碱是非竞争性抑制剂。我们的数据表明线粒体能够摄取阿霉素并将其浓缩在基质中，正如已知其他带正电荷的化合物所发生的情况一样。发现与线粒体内膜结合的阿霉素比外膜更多；这可能是由于内膜的蛋白质含量更高，而不是药物与心磷脂结合。尽管先前认为抑制心脏内膜肉碱棕榈酰转移酶是阿霉素心脏毒性机制的一部分，但目前关于阿霉素及其无心脏毒性类似物的研究结果并不支持这一观点。
