Turton J A, Andrews C M, Havard A C, Robinson S, York M, Williams T C, Gibson F M
Centre for Toxicology, Department of Pharmacology, The School of Pharmacy, University of London, 29/39 Brunswick Square, UK.
Food Chem Toxicol. 2002 Dec;40(12):1849-61. doi: 10.1016/s0278-6915(02)00178-3.
Chloramphenicol (CAP) is haemotoxic in man, inducing two forms of toxicity. First, a commonly-occurring, dose-related, reversible bone marrow depression, which develops during treatment. Second, a rarer aplastic anaemia (AA), developing after treatment, is irreversible, and often fatal. Thiamphenicol (TAP) was developed as a replacement for CAP; however, there are no toxicological investigations in the mouse or rat on the dose-related haemotoxicity of TAP, in repeat dose gavage studies. Therefore, we have conducted a comprehensive investigation in these species, administering TAP for 7-17 days, to define haematological changes. Female BALB/c mice were gavaged with TAP, daily for 7-17 days at 400-1500 mg/kg; female Wistar Hanover rats were dosed with TAP daily at 50-375 mg/kg for 9 or 10 days. Haematological changes were studied at 1, 7 and 14 days post-dosing. In mice at day 1, TAP caused decreases in RBC, HCT and Hb; reticulocytes and platelets were reduced; changes were dose-related and reversible. Marrow cell counts were reduced; marrow was hypocellular, with erythroid depletion and progenitor cell vacuolation; the myeloid/erythroid (M:E) ratio was increased. In the rat, changes were not as clear-cut; there was anaemia with indications of reduced reticulocyte and platelet counts, and evidence of decreased neutrophils and lymphocytes. Marrow erythroid cells were decreased, precursor cells vacuolated, and the M:E ratio increased. We conclude that TAP induced haematological changes in the mouse and rat, parallelling the dose-dependent, reversible marrow depression reported in man; TAP is more haemotoxic in the rat than in the mouse.
氯霉素（CAP）对人类具有血液毒性，可引发两种毒性形式。其一，是一种常见的、与剂量相关的、可逆的骨髓抑制，在治疗期间出现。其二，是一种较为罕见的再生障碍性贫血（AA），在治疗后发生，不可逆，且往往致命。甲砜霉素（TAP）作为CAP的替代品而被研发；然而，在重复剂量灌胃研究中，尚未对小鼠或大鼠进行关于TAP剂量相关血液毒性的毒理学研究。因此，我们在这些物种中进行了全面研究，给予TAP 7至17天，以确定血液学变化。雌性BALB/c小鼠每天以400至1500 mg/kg的剂量灌胃给予TAP，持续7至17天；雌性Wistar Hanover大鼠每天以50至375 mg/kg的剂量给予TAP，持续9或10天。在给药后第1、7和14天研究血液学变化。在小鼠中，给药第1天，TAP导致红细胞（RBC）、血细胞比容（HCT）和血红蛋白（Hb）降低；网织红细胞和血小板减少；变化与剂量相关且可逆。骨髓细胞计数减少；骨髓细胞减少，有红系细胞减少和祖细胞空泡化；髓系/红系（M:E）比值增加。在大鼠中，变化不那么明显；出现贫血，伴有网织红细胞和血小板计数降低的迹象，以及中性粒细胞和淋巴细胞减少的证据。骨髓红系细胞减少，前体细胞空泡化，M:E比值增加。我们得出结论，TAP在小鼠和大鼠中诱导了血液学变化，与人类中报道的剂量依赖性、可逆性骨髓抑制相似；TAP在大鼠中的血液毒性比在小鼠中更强。
