Matthews J H, Shiels S, Wickramasinghe S N
Dept. of Haematology, St Mary's Hospital Medical School, London, U.K.
Eur J Haematol. 1990 Jul;45(1):43-7. doi: 10.1111/j.1600-0609.1990.tb00413.x.
To help understand the pathogenesis of megaloblastic anaemia, we have studied folate-deprived HL60 cells. Cells grown with no added folic acid developed macrocytosis, a prolonged doubling time, a grossly increased deoxyuridine-suppressed value, and markedly reduced thymidylate synthetase activity. Cells in medium containing 50 nmol/l added folic acid became macrocytic with similar biochemical changes, but their doubling time was only marginally prolonged. In 100 nmol/l added folic acid, there was slight macrocytosis and a normal doubling time, but marked biochemical alterations were still present. The findings demonstrate that folate deficiency causes diminished thymidylate synthetase activity and macrocytosis in human myeloid cells, but that such cells may nevertheless demonstrate no prolongation of their doubling time, indicating either that their supply of thymidine triphosphate (TTP) is sufficient, or that misincorporation of deoxyuridine triphosphate (dUTP) is occurring. This suggests that the ineffectiveness of haemopoiesis in folate deficiency may result from damage to bone marrow cells in some way other than arrest in S-phase by a reduced delivery of TTP to the DNA replication fork.
为了帮助理解巨幼细胞贫血的发病机制，我们研究了缺乏叶酸的HL60细胞。在不添加叶酸的情况下培养的细胞出现了大细胞性贫血、加倍时间延长、脱氧尿苷抑制值大幅增加以及胸苷酸合成酶活性显著降低。在添加了50 nmol/l叶酸的培养基中的细胞也出现了大细胞性贫血，并伴有类似的生化变化，但它们的加倍时间仅略有延长。在添加了100 nmol/l叶酸的情况下，有轻微的大细胞性贫血，加倍时间正常，但仍存在明显的生化改变。这些发现表明，叶酸缺乏会导致人类髓系细胞中胸苷酸合成酶活性降低和大细胞性贫血，但这些细胞的加倍时间可能不会延长，这表明它们的三磷酸胸苷（TTP）供应充足，或者脱氧三磷酸尿苷（dUTP）的错误掺入正在发生。这表明叶酸缺乏时造血功能无效可能是由于骨髓细胞受到损害，其方式不同于因TTP向DNA复制叉的递送减少而导致S期停滞。
