Lipschik G Y, Masur H, Kovacs J A
Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland 20892.
J Infect Dis. 1991 May;163(5):1121-7. doi: 10.1093/infdis/163.5.1121.
Alpha-difluoromethylornithine (DFMO) is being used to treat Pneumocystis carinii pneumonia despite a lack of in vitro evidence supporting its antipneumocystis activity. DFMO is a specific inhibitor of ornithine decarboxylase, the rate-limiting enzyme of polyamine biosynthesis. To investigate polyamine metabolism in P. carinii, extracts of the organism were analyzed for polyamine content and ornithine decarboxylase activity, and [3H]ornithine and [14C]arginine incorporation into polyamines during short-term culture was determined. P. carinii extracts contained putrescine and spermidine in a ratio of 0.17:1; traces of spermine were detected. Although ornithine decarboxylase activity was not detected, P. carinii incorporated ornithine and arginine into putrescine and spermidine but not into spermine, suggesting that the spermine detected derived from contaminating host cells. Uninfected rat lung incorporated ornithine minimally. Pentamidine, DFMO, and alpha-monofluoromethyldehydroornithine methyl ester inhibited ornithine incorporation by up to 86% at clinically achievable concentrations. These data provide a rationale for using polyamine synthesis antagonists in P. carinii pneumonia and a method for screening antipneumocystis drugs in vitro.
尽管缺乏体外证据支持其抗卡氏肺孢子虫活性，但α-二氟甲基鸟氨酸（DFMO）仍被用于治疗卡氏肺孢子虫肺炎。DFMO是鸟氨酸脱羧酶的特异性抑制剂，鸟氨酸脱羧酶是多胺生物合成的限速酶。为了研究卡氏肺孢子虫中的多胺代谢，分析了该生物体提取物中的多胺含量和鸟氨酸脱羧酶活性，并测定了短期培养过程中[3H]鸟氨酸和[14C]精氨酸掺入多胺的情况。卡氏肺孢子虫提取物中腐胺和亚精胺的比例为0.17:1；检测到痕量的精胺。虽然未检测到鸟氨酸脱羧酶活性，但卡氏肺孢子虫将鸟氨酸和精氨酸掺入腐胺和亚精胺中，而不掺入精胺，这表明检测到的精胺源自污染的宿主细胞。未感染的大鼠肺组织掺入的鸟氨酸极少。在临床可达到的浓度下，戊烷脒、DFMO和α-单氟甲基脱氢鸟氨酸甲酯可将鸟氨酸掺入抑制高达86%。这些数据为在卡氏肺孢子虫肺炎中使用多胺合成拮抗剂提供了理论依据，并提供了一种体外筛选抗卡氏肺孢子虫药物的方法。
