Combs A B, Acosta D
Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas, Austin 78712.
Toxicol Pathol. 1990;18(4 Pt 1):583-96.
Toxic injury is one of the many ways by which the functional integrity of the heart may become compromised. Any of the subcellular elements may be the target of toxic injury, including all of the various membranes and organelles. Understanding the mechanisms underlying cardiotoxicity may lead to treatment of the toxicity or to its prevention. Doxorubicin and its analogs are very important cancer chemotherapeutic agents that can cause cardiotoxicity. Other agents which are cardiotoxic and which have profound public health implications include the alkaloid emetine in ipecac syrup, cocaine, and ethyl alcohol. The most important cardiotoxic mechanisms proposed for doxorubicin include oxidative stress with its resultant damage to myocardial elements, changes in calcium homeostasis, decreased ability to produce ATP, and systemic release of cardiotoxic humoral mediators from tissue mast cells. Each of the first 3 mechanisms can lead to each of the other 2, and the causal relationships between all of these mechanisms are not clear. New evidence suggests that doxorubicinol, one of the metabolites of doxorubicin may be the moiety responsible for cardiotoxicity. Several other potential mechanisms also have been proposed for doxorubicin. Emetine in ipecac syrup is the first aid treatment of choice for many acute toxic oral ingestions and the alkaloid, itself, is used to treat amebiasis. Cardiotoxicity occurs following chronic exposure, such as occurs therapeutically in amebiasis and with ipecac abuse by bulemics. A number of mechanisms are proposed for emetine cardiotoxicity, but the current mechanistic literature is quite scarce. Cocaine abuse recently has caught the public interest, in particular because of the drug-related sudden deaths of certain athletes. Cocaine can cause hypertension, arrhythmias, and reduced coronary blood flow, each of which can contribute to its lethality. However, it may be possible that cocaine sudden death episodes are more related to hyperthermia and convulsive seizures, rather than to cardiovascular toxicity. Chronic alcohol use leads to dilated cardiomyopathy and failure as part of the general physical degeneration that occurs with alcoholism. Several mechanisms are proposed for the cardiomyopathy, but only 2 things seem clear. The cardiotoxicity is due to an intrinsic effect of alcohol, rather than to malnutrition or co-toxicity, and abstinence is the only effective treatment for the cardiomyopathy. Recent articles indicate that very moderate use of alcohol may be beneficial and protect against cardiovascular-related morbidity. One explanation for these findings seems to be that the non-drinking groups, against whom the moderate drinking comparisons were made, were enriched in former drinkers with significant alcohol-related cardiovascular pathology.
毒性损伤是心脏功能完整性可能受损的众多方式之一。任何亚细胞成分都可能成为毒性损伤的靶点，包括所有各种膜和细胞器。了解心脏毒性的潜在机制可能会带来对毒性的治疗或预防。阿霉素及其类似物是非常重要的癌症化疗药物，但可导致心脏毒性。其他具有心脏毒性且对公众健康有深远影响的药物包括吐根糖浆中的生物碱吐根碱、可卡因和乙醇。针对阿霉素提出的最重要的心脏毒性机制包括氧化应激及其对心肌成分的损伤、钙稳态的变化、产生三磷酸腺苷（ATP）的能力下降以及组织肥大细胞释放心脏毒性体液介质。前三种机制中的每一种都可能导致另外两种机制的出现，而所有这些机制之间的因果关系尚不清楚。新证据表明，阿霉素的代谢产物之一阿霉素醇可能是导致心脏毒性的部分原因。针对阿霉素还提出了其他几种潜在机制。吐根糖浆中的吐根碱是许多急性经口中毒的首选急救治疗药物，这种生物碱本身用于治疗阿米巴病。慢性接触后会发生心脏毒性，如在治疗阿米巴病时以及神经性贪食症患者滥用吐根糖浆时。针对吐根碱心脏毒性提出了多种机制，但目前关于机制的文献相当匮乏。可卡因滥用最近引起了公众的关注，特别是因为某些运动员与药物相关的猝死。可卡因可导致高血压、心律失常和冠状动脉血流减少，每一种都可能导致其致命性。然而，可卡因猝死事件可能更多地与体温过高和惊厥发作有关，而不是与心血管毒性有关。长期饮酒会导致扩张型心肌病和心力衰竭，这是酗酒导致的全身身体退化的一部分。针对心肌病提出了多种机制，但似乎只有两点是明确的。心脏毒性是由于酒精的内在作用，而不是由于营养不良或共同毒性，戒酒是治疗心肌病的唯一有效方法。最近的文章表明，非常适度地饮酒可能有益，并能预防心血管相关疾病。对这些发现的一种解释似乎是，与适度饮酒进行比较的不饮酒组中，前饮酒者比例较高，他们有明显的与酒精相关的心血管疾病。
