Tucker A N, Hong L, Boorman G A, Pung O, Luster M I
J Pharmacol Exp Ther. 1985 Jul;234(1):57-62.
Female B6C3F1 mice were administered the anticonvulsant drug diphenylhydantoin (DPH) for 1 to 4 weeks by gavage at doses of 25 to 200 mg/kg. None of the dosing regimens caused toxicological manifestations other than hepatomegaly. Evaluation of the immune status of the drug-treated mice revealed no alteration of cellular immunity, measured by delayed hypersensitivity response and lymphocyte responsiveness to mitogens or allogeneic leukocytes. Humoral immunity, as measured by serum immunoglobulin quantitation and plaque-forming cell response to sheep erythrocytes, was depressed by DPH at 100 mg/kg after 2 weeks, as was host resistance to infection with the parasite Plasmodium yoelii. The bone marrow was the most sensitive target organ with loss of the multipotent stem cell colony-forming unit-spleen occurring within 1 week at a dose of 50 mg/kg. The colony-forming unit-spleen suppression was the result of a selective loss of stem cells in S phase. Committed granulocyte macrophage progenitor cells, colony-forming unit-granulocyte macrophage, were also inhibited by DPH in vivo, as well as in vitro at concentrations as low as 0.2 microM. Bone marrow cells from DPH-treated mice were folate deficient, as determined by the inability of these cells to convert deoxyuridine to thymidine. However, these mice had normal serum folate levels, even after 4 weeks of treatment. Folic acid protected bone marrow stem cells after both in vivo and in vitro treatment with DPH. It is suggested that DPH inhibits folate utilization or metabolism at the cellular level, selectively affecting bone marrow stem cells and resulting in altered stem cell kinetics. This lesion ultimately results in altered humoral immunity and impaired host resistance.
对雌性B6C3F1小鼠经口灌胃给予抗惊厥药物苯妥英（DPH），剂量为25至200mg/kg，持续1至4周。除肝肿大外，所有给药方案均未引起毒理学表现。对经药物处理的小鼠的免疫状态评估显示，通过迟发型超敏反应以及淋巴细胞对有丝分裂原或同种异体白细胞的反应性所测定的细胞免疫没有改变。以血清免疫球蛋白定量和对绵羊红细胞的空斑形成细胞反应来衡量，体液免疫在2周后受到100mg/kg DPH的抑制，对约氏疟原虫感染的宿主抵抗力也受到抑制。骨髓是最敏感的靶器官，在50mg/kg剂量下，多能干细胞脾集落形成单位在1周内丧失。脾集落形成单位的抑制是S期干细胞选择性丧失的结果。定向粒细胞巨噬细胞祖细胞，即粒细胞巨噬细胞集落形成单位，在体内以及体外低至0.2μM的浓度下也受到DPH的抑制。经DPH处理的小鼠的骨髓细胞叶酸缺乏，这是通过这些细胞无法将脱氧尿苷转化为胸苷来确定的。然而，即使在治疗4周后，这些小鼠的血清叶酸水平仍正常。叶酸在用DPH进行体内和体外处理后均可保护骨髓干细胞。提示DPH在细胞水平上抑制叶酸利用或代谢，选择性地影响骨髓干细胞并导致干细胞动力学改变。这种损伤最终导致体液免疫改变和宿主抵抗力受损。
