Experimental neurotoxicity of 5-fluorouracil and its derivatives is due to poisoning by the monofluorinated organic metabolites, monofluoroacetic acid and α-fluoroβ-alanine
Experimental neurotoxicity of 5-fluorouracil and its derivatives is due to poisoning by the monofluorinated organic metabolites, monofluoroacetic acid and α-fluoroβ-alanine
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5-氟尿嘧啶及其衍生物的实验性神经毒性是由于单氟有机代谢物、单氟乙酸和α-氟β-丙氨酸中毒所致
作者：
R. Okeda;M. Shibutani;T. Matsuo;T. Kuroiwa;R. Shimokawa;T. Tajima
本实验采用5-氟尿嘧啶（FU）的两种代谢产物--单氟乙酸（FA）和α-氟-β-丙氨酸（FBAL），经猫左心室连续给药1个月，以探讨FU及其衍生物的神经毒性机制。1个月期间FU和FBAL的累积剂量分别为1.5-45 mg（20只猫）和0.2-4.8 mg（21只猫）。作为每个实验组的对照，施用乙酸（AA）和β-丙氨酸（BAL）。在与累积剂量和分子量相关的生存时间方面，FBAL比FA毒性更大。神经病理学检查可见空泡和坏死/软化样改变，空泡直径20-50 μm，主要分布于小脑核、白色质和脑干顶盖、被盖。电镜下，这些空泡是由于髓鞘间期线分裂或轴突与髓鞘最内层分离所致。坏死/软化样改变优先发生在FBAL组，对称地位于上级和下丘、眼神经核和丘脑。两种类型的神经病理学变化，尤其是FBAL组，与经口给予FU及其衍生物的猫中发现的相似。因此，可以得出结论，FU及其衍生物在犬和猫中的亚急性和慢性神经毒性是由于单氟有机代谢物FA和FBAL中毒所致，FA和FBAL对髓鞘的直接作用以及FBAL对中脑能量代谢或血管的作用被认为是主要的致病因素。
SummaryTwo metabolites of 5-fluorouracil (FU), monofluoroacetic acid (FA) and α-fluoro-β-alanine (FBAL), were continuously administered into the left ventricle of the brain in cats for up to 1 month to investigate the mechanissm of neurotoxicity of FU and its derivatives. The cumulative doses of FU and FBAL over a 1-month period were 1.5–45 mg (20 cats) and 0.2–4.8 mg (21 cats), respectively. As controls for each experimental group, acetic acid (AA) and β-alanine (BAL) were administered. In terms of survival time in relation to the cumulative dose and molecular weight, FBAL was more toxic than FA. Neuropathologically, two types of change, vacuoles and necrosis/softening-like change, were found. The vacuoles were 20–50 μm in diameter, and distributed mainly in the cerebellar nuclei, white matter and the tectum and tegmentum of the brain stem in both experimental groups. Electron microscopically, these vacuoles were due to splitting of the myelin intraperiod line or separation between the axon and the innermost layer of myelin. Necrosis/softening-like change occurred preferentially in the FBAL group and was located symmetrically in the superior and inferior colliculi, oculomotor nuclei and thalamus. Both types of neuropathological change, especially those in the FBAL group, were similar to those found in cats orally administered with FU and its derivatives. It was, therefore, concluded that the subacute and chronic neurotoxicity of FU and its derivatives in dogs and cats is due to intoxication with the monofluorinated organic metabolites, FA and FBAL, and that the direct action of FA and FBAL on myelin and the action of FBAL on energy metabolism or vessels of the mid brain were proposed as the main pathogenetic factor involved.