Spielberg S P
Strategic Operations, Clinical and Regulatory Development, Merck Research Laboratories, Blue Bell, PA 19422, USA.
Eur J Haematol Suppl. 1996;60:93-7. doi: 10.1111/j.1600-0609.1996.tb01653.x.
Pharmacogenetic differences in the handling of and response to drugs can markedly alter the risk of severe idiosyncratic adverse drug reactions, including neutropenia, agranulocytosis and aplastic anaemia. Inherited deficiencies of drug metabolizing enzymes can shunt the metabolism of drugs to metabolites which are directly toxic (e.g. 6-mercaptopurine metabolism to 6-thioguanine nucleotides) or towards electrophilic metabolites which can kill cells and/or lead to a host immune response (e.g. sulphonamide metabolism to hydroxylamine metabolites). Defects in detoxification pathways (e.g. glutathione conjugation) similarly can predispose patients to adverse outcomes. The advent of molecular screening tools to define individual (rather than population) risk may lead to the use of clinical laboratory tests to identify/predict idiosyncratic adverse drug reactions.
药物处理和反应中的药物遗传学差异可显著改变严重特异质性药物不良反应的风险，包括中性粒细胞减少、粒细胞缺乏症和再生障碍性贫血。药物代谢酶的遗传性缺陷可使药物代谢转向直接有毒的代谢产物（如6-巯基嘌呤代谢为6-硫鸟嘌呤核苷酸）或亲电子代谢产物，后者可杀死细胞和/或引发宿主免疫反应（如磺胺代谢为羟胺代谢产物）。解毒途径（如谷胱甘肽结合）的缺陷同样可使患者易出现不良后果。定义个体（而非群体）风险的分子筛查工具的出现可能会促使使用临床实验室检测来识别/预测特异质性药物不良反应。
