药物诱发的卟啉病

Drug‑induced porphyrias

卟啉病是由于血红素生物合成过程中酶缺陷导致卟啉及卟啉前体物质蓄积而致病的一组代谢性疾病。卟啉病基因携带者使用卟啉原性药物是引起严重急性卟啉病发作(APA)的主要诱因。肝脏δ-氨基乙酰丙酸合成酶1(ALAS1)是血红素生物合成链的限速酶,受肝脏游离血红素池的负反馈调节。药物诱发APA的核心机制是药物在肝脏中通过多种途径诱导ALAS1的转录合成增多,卟啉病基因携带者的先天性酶缺陷则成为限速步骤,卟啉或前体物质不能够转化成血红蛋白而在体内大量蓄积,引起APA。通过临床经验、药物化学结构及作用机制、细胞及动物实验数据预测药物的卟啉原性能指导临床用药、降低APA风险,但预测准确性还有待临床实践用药数据来验证,而且卟啉病基因携带者对卟啉原性药物的反应也具有显著可变性。对卟啉病基因携带者开具处方时,需要高度警惕药物诱发卟啉病的潜在风险,慎重选择药物,同时也应避免用药过于谨慎延误其他疾病的治疗。

Porphyrias are a group of metabolic disorders caused by the accumulation of porphyrin and its precursor substances due to enzyme defects in heme biosynthesis.The use of porphyrinogenic drugs is the main inducement of severe acute porphyria attack(APA)in porphyria gene carriers.Delta‑aminolevulinic acid synthase 1(ALAS1)in the liver is the rate‑limiting enzyme of heme biosynthesis chain,which is negatively regulated by the free heme pool in liver.The core mechanism of drug‑triggered APA is that drugs induce increases of the transcription and synthesis of ALAS1 in the liver through various pathways,congenital enzyme defect becomes the rate‑determining step in porphyria gene carriers,a large amount of porphyrin or precursor substances accumulate in the body due to the inability to convert them into hemoglobin,and thereby APA occurs.Predicting the porphyrogenicity of drugs according to clinical experience and the chemical structure,action mechanism,cell and animal test data of drugs can provide guidance to APA use in clinic and reduce its medication risk.However,the accuracy of prediction needs to be verified by medication data in clinical practices,and the response to porphyrinogenic drugs in porphyria gene carriers also has significant variabilities.When prescribing for porphyria gene carriers,potential risks of drug‑triggered porphyria should be highly vigilant about,and drugs selection should be carefully;the delay of the treatment of other diseases due to using drugs too cautiously also should be avoided.