Herman E H, Zhang J, Hasinoff B B, Tran K T, Chadwick D P, Clark J R, Ferrans V J
Division of Applied Pharmacology Research, Food and Drug Administration, Laurel, MD 20708, USA.
Toxicology. 1998 Jun 26;128(1):35-52. doi: 10.1016/s0300-483x(98)00049-3.
Comparisons were made of the toxic effects produced in the heart, kidney and small intestine of spontaneously hypertensive rats (SHR) by the administration of 12 consecutive weekly doses of doxorubicin (1 mg/kg), and high, intermediate and low doses of piroxantrone (3, 1.5 and 0.75 mg/kg) and losoxantrone (1, 0.5 and 0.25 mg/kg). Animals receiving saline were used as controls. The toxicities of the three drugs were evaluated by clinical chemistry and hematological determinations, light microscopy and transmission electron microscopy. The severity of the histologic alterations in heart, kidney and small intestine was assessed semiquantitatively. Biochemical and molecular modeling studies were made to evaluate the formation of complexes of Fe(III) with piroxantrone and losoxantrone. The cardiac (myofibrillar loss and dilatation of the sarcoplasmic reticulum) and renal (glomerular vacuolization, tubular damage and laboratory evidence of a nephrotic syndrome) lesions induced by all three agents had similar features. However, the cardiac lesions induced by losoxantrone and doxorubicin were significantly more severe (Billingham scores) than those produced by piroxantrone. The renal lesions induced by piroxantrone and losoxantrone were less severe than those produced by doxorubicin. Similarly losoxantrone and piroxantrone-induced intestinal alterations (denudation of epithelial layer and inflammatory cellular infiltration) were less severe than those occurring after treatment with doxorubicin. Both losoxantrone and piroxantrone were shown to form Fe(III): drug complexes that may cause oxidative damage to various tissues.
对自发性高血压大鼠（SHR）连续12周每周给药阿霉素（1毫克/千克）、高、中、低剂量的吡罗蒽醌（3、1.5和0.75毫克/千克）和洛索蒽醌（1、0.5和0.25毫克/千克）后在心脏、肾脏和小肠产生的毒性作用进行了比较。接受生理盐水的动物用作对照。通过临床化学和血液学测定、光学显微镜和透射电子显微镜评估这三种药物的毒性。对心脏、肾脏和小肠组织学改变的严重程度进行半定量评估。进行了生化和分子模型研究以评估Fe(III)与吡罗蒽醌和洛索蒽醌形成复合物的情况。所有三种药物诱导的心脏（肌原纤维丧失和肌浆网扩张）和肾脏（肾小球空泡化、肾小管损伤和肾病综合征的实验室证据）病变具有相似特征。然而，洛索蒽醌和阿霉素诱导的心脏病变（比林厄姆评分）比吡罗蒽醌引起的病变严重得多。吡罗蒽醌和洛索蒽醌诱导的肾脏病变比阿霉素引起的病变轻。同样，洛索蒽醌和吡罗蒽醌诱导的肠道改变（上皮层剥脱和炎性细胞浸润）比阿霉素治疗后发生的改变轻。洛索蒽醌和吡罗蒽醌均显示形成Fe(III)：药物复合物，可能对各种组织造成氧化损伤。
