Salvatorelli Emanuela, Menna Pierantonio, Cascegna Sabrina, Liberi Giovanni, Calafiore Antonio M, Gianni Luca, Minotti Giorgio
Department of Drug Sciences and Center of Excellence on Aging, G. d'Annunzio University School of Medicine, Via dei Vestini, 66013 Chieti, Italy.
J Pharmacol Exp Ther. 2006 Jul;318(1):424-33. doi: 10.1124/jpet.106.103846. Epub 2006 Apr 13.
Antitumor therapy with the anthracycline doxorubicin is limited by a dose-related cardiotoxicity that is aggravated by a concomitant administration of the taxane paclitaxel. Previous limited studies with isolated human heart cytosol showed that paclitaxel was able to stimulate an NADPH-dependent reduction of doxorubicin to its toxic secondary alcohol metabolite doxorubicinol. Here we characterized that 0.25 to 2.5 microM paclitaxel caused allosteric effects that increased doxorubicinol formation in human heart cytosol, whereas 5 to 10 microM paclitaxel decreased doxorubicinol formation. The closely related taxane docetaxel caused similar effects. Basal or taxane-stimulated doxorubicinol formation was blunted by 2,7-difluorospirofluorene-9,5'-imidazolidine-2',4'-dione (AL1576), a specific inhibitor of aldehyde reductases. Doxorubicinol was measured also in the cytosol of human myocardial strips incubated in plasma and exposed to doxorubicin in the absence or presence of paclitaxel or docetaxel and their clinical vehicles Cremophor EL or polysorbate 80. Low concentrations of taxanes stimulated doxorubicinol formation, whereas high concentrations decreased it. Doxorubicinol formation reached its maximum on adding plasma with 6 microM paclitaxel or docetaxel; this corresponded to the partitioning of 1.5 to 2.5 microM taxanes in the cytosol of the strips. Taxane-stimulated doxorubicinol formation was not mediated by vehicles, nor was it caused by increased doxorubicin uptake or de novo protein synthesis; however, doxorubicinol formation was blunted by AL1576. These results show that allosteric interactions with cytoplasmic aldehyde reductases enable paclitaxel or docetaxel to stimulate doxorubicinol formation in human heart. This information serves metabolic insights into the risk of cardiotoxicity induced by doxorubicin-taxane therapies.
蒽环类药物阿霉素的抗肿瘤治疗受到剂量相关心脏毒性的限制，而紫杉烷类药物紫杉醇的同时给药会加重这种毒性。先前对分离的人心脏细胞溶质进行的有限研究表明，紫杉醇能够刺激阿霉素依赖NADPH还原为其有毒的仲醇代谢物阿霉素醇。在此，我们发现0.25至2.5微摩尔/升的紫杉醇会产生变构效应，增加人心脏细胞溶质中阿霉素醇的形成，而5至10微摩尔/升的紫杉醇则会减少阿霉素醇的形成。密切相关的紫杉烷类药物多西他赛也产生了类似的效果。2,7-二氟螺芴-9,5'-咪唑烷-2',4'-二酮（AL1576）是醛还原酶的特异性抑制剂，它会抑制基础或紫杉烷刺激的阿霉素醇形成。在含有血浆并暴露于阿霉素的人心肌条带的细胞溶质中，也检测了阿霉素醇，这些心肌条带分别在不存在或存在紫杉醇、多西他赛及其临床载体聚氧乙烯蓖麻油（Cremophor EL）或聚山梨酯80的情况下进行培养。低浓度的紫杉烷类药物刺激阿霉素醇的形成，而高浓度则会降低其形成。在添加含有6微摩尔/升紫杉醇或多西他赛的血浆时，阿霉素醇的形成达到最大值；这相当于条带细胞溶质中1.5至2.5微摩尔/升紫杉烷类药物的分配量。紫杉烷刺激的阿霉素醇形成不是由载体介导的，也不是由阿霉素摄取增加或从头蛋白质合成引起的；然而，AL1576会抑制阿霉素醇的形成。这些结果表明，与细胞质醛还原酶的变构相互作用使紫杉醇或多西他赛能够刺激人心脏中阿霉素醇的形成。该信息有助于深入了解阿霉素-紫杉烷疗法诱导心脏毒性风险的代谢机制。
