Olson J W, Atkinson J E, Hacker A D, Altiere R J, Gillespie M N
Toxicol Appl Pharmacol. 1985 Oct;81(1):91-9. doi: 10.1016/0041-008x(85)90124-3.
Previous work in our laboratory has shown that the continuous administration of alpha-difluoromethylornithine (DFMO), a highly specific irreversible inhibitor of ornithine decarboxylase (ODC), which is the rate-limiting enzyme in polyamine biosynthesis, prevented the development of pulmonary hypertension and right ventricular hypertrophy induced in rats 21 days after a single injection of monocrotaline (MCT). We now report that DFMO treatment did not influence the proposed first step of MCT pneumotoxicity, that is, the hepatic metabolism of MCT to toxic pyrrolic metabolites. In contrast, DFMO treatment blunted the development of lung perivascular edema at Day 7, inhibited the respective four- and twofold increases in lung putrescine and spermidine contents at Day 21 without significantly altering spermine content, and prevented the arterial medial thickening at Day 21. It thus appears that increased lung polyamine biosynthesis may be essential for the expression of MCT-induced perivascular edema as well as the development of the medial thickening stage of MCT-induced hypertensive pulmonary vascular disease.
我们实验室之前的研究表明，持续给予α-二氟甲基鸟氨酸（DFMO），一种鸟氨酸脱羧酶（ODC）的高度特异性不可逆抑制剂，而ODC是多胺生物合成中的限速酶，可预防单次注射野百合碱（MCT）21天后大鼠发生的肺动脉高压和右心室肥大。我们现在报告，DFMO治疗并不影响所提出的MCT肺毒性的第一步，即MCT在肝脏代谢为有毒的吡咯代谢产物。相反，DFMO治疗在第7天减轻了肺血管周围水肿的发展，抑制了第21天肺中腐胺和亚精胺含量分别增加四倍和两倍，而精胺含量没有显著改变，并预防了第21天的动脉中层增厚。因此，似乎肺多胺生物合成增加对于MCT诱导的血管周围水肿的表达以及MCT诱导的高血压性肺血管疾病中层增厚阶段的发展可能至关重要。
