Halliwell W H
Schering-Plough Research Institute, Lafayette, New Jersey 07848, USA.
Toxicol Pathol. 1997 Jan-Feb;25(1):53-60. doi: 10.1177/019262339702500111.
Phospholipidosis, a phospholipid storage disorder, defines an excessive accumulation of intracellular phospholipids. Phospholipids are structural components of mammalian cytoskeleton and cell membranes. The metabolism of this essential cell component is regulated by the individual cell and may be altered by drugs that interact with phospholipids or the enzymes that affect their metabolism. Xenobiotics or their metabolites that induce phospholipidosis include a wide variety of pharmacologic agents, including antibacterials, antipsychotics, antidepressants, antiarrhythmics, antianginals, antimalarials, anorexic agents, cholesterol-lowering agents, and others. Each of these drugs shares several common physiochemical properties: hydrophobic ring structure on the molecule and a hydrophilic side chain with a charged cationic amine group, hence the class term cationic amphiphilic drugs (CADs). This paper reviews the phospholipid metabolism, physiochemical characteristics of CADs, specificity of phospholipidosis in animals and humans, functional effects of phospholipidosis, interaction of CADs with biologic membranes and lysosome metabolism, influence of CADs on phospholipases and phospholipid synthesis, and a proposed mechanism for induction of phospholipidosis in the lung. In human risk assessment, investigators should consider the many factors in evaluating a drug that induces phospholipidosis in animals. These include: the therapeutic class of drug, presence of active metabolites, tissue or organ selectivity in animals and humans, influence of concurrently administered drugs, reversibility of effect, and other factors that increase or decrease the induction of phospholipidosis. Generalities regarding the etiology, incidence, and effect of the drug on a specific host may not be made. Each drug must be evaluated separately to identify the risk when administered for therapeutic effect in humans.
磷脂贮积病是一种磷脂储存障碍性疾病，其定义为细胞内磷脂过度蓄积。磷脂是哺乳动物细胞骨架和细胞膜的结构成分。这种重要细胞成分的代谢由单个细胞调节，可能会受到与磷脂相互作用的药物或影响其代谢的酶的改变。诱导磷脂贮积病的外源性物质或其代谢产物包括多种药理剂，如抗菌药、抗精神病药、抗抑郁药、抗心律失常药、抗心绞痛药、抗疟药、食欲抑制剂、降胆固醇药等。这些药物中的每一种都具有几个共同的物理化学性质：分子上的疏水环结构和带有带电荷阳离子胺基的亲水侧链，因此这类药物被称为阳离子两亲性药物（CADs）。本文综述了磷脂代谢、CADs的物理化学特性、动物和人类磷脂贮积病的特异性、磷脂贮积病的功能影响、CADs与生物膜和溶酶体代谢的相互作用、CADs对磷脂酶和磷脂合成的影响，以及肺部磷脂贮积病诱导的一种 proposed 机制。在人类风险评估中，研究人员在评估一种在动物中诱导磷脂贮积病的药物时应考虑许多因素。这些因素包括：药物的治疗类别、活性代谢产物的存在、动物和人类中的组织或器官选择性、同时给药药物的影响、效应的可逆性，以及增加或减少磷脂贮积病诱导的其他因素。不能对药物的病因、发病率及其对特定宿主的影响进行一概而论。每种药物都必须单独评估，以确定在人类中用于治疗效果时的风险。 （注：“proposed”未准确翻译，因原文此处可能有误，推测可能是“proposed”，意为“提出的”，但不明确确切含义，故保留原文）
