de Castro C R, De Toranzo E G, Carbone M, Castro J A
Centro de Investigaciones Toxicológicas (CEITOX) CITEFA/CONICET, Provincia de Buenos Aires, Argentina.
Exp Mol Pathol. 1990 Feb;52(1):98-108. doi: 10.1016/0014-4800(90)90062-i.
Nifurtimox (Nfx) (4(5-nitrofurfurylidene)amino)-3-methylthiomorpholine-1, 1-dioxide) is a drug used against Chagas' disease, a parasitic sickness afflicting several million Latin Americans. Nfx administration to Sprague-Dawley male rats (220-250 g) at a dose of 100 mg/kg caused pronounced alterations in the adrenal cortex involving the fasciculata and reticularis zones but which were not evident in the glomerulosa. Alterations observed involved mitochondria, nuclei, Golgi apparatus, and the endoplasmic reticulum but were more intense in the mitochondria. There is Nfx nitroreductase activity in the adrenal microsomal, mitochondrial, and cytosolic-rich fractions but most of it is in the mitochondrial-rich fraction. Activity in the first two fractions requires NADPH and that in the cytosol is only observed in the presence of hypoxanthine as substrate. Enzymatic activity in all fractions is inhibited by oxygen. CO does not inhibit mitochondrial Nfx nitroreductase and inhibits only 10% of the microsomal enzyme activity. Hypoxanthine-dependent cytosolic activity is inhibited by allopurinol. Present results suggest that Nfx is activated to damage-producing reactive metabolites by nitroreductive biotransformation in rat adrenal organelles. Mitochondrial and microsomal bioactivation would occur at the level of the flavoenzyme P-450 reductase rather than at P-450 itself, and cytosolic bioactivation would be mediated by xanthine oxidase. Epidemiological studies on adrenal function in patients undergoing Nfx treatment would be necessary to establish the potential toxicological relevance of these findings.
硝呋替莫（Nfx）（4-（5-硝基糠叉基）氨基-3-甲基硫代吗啉-1,1-二氧化物）是一种用于治疗恰加斯病的药物，这种寄生虫病折磨着数百万拉丁美洲人。以100mg/kg的剂量给体重220-250g的雄性Sprague-Dawley大鼠施用Nfx，会导致肾上腺皮质明显改变，累及束状带和网状带，但在球状带不明显。观察到的改变涉及线粒体、细胞核、高尔基体和内质网，但在线粒体中更明显。肾上腺微粒体、线粒体和富含胞质的部分存在Nfx硝基还原酶活性，但大部分活性存在于富含线粒体的部分。前两个部分的活性需要NADPH，而胞质中的活性仅在次黄嘌呤作为底物时才观察到。所有部分的酶活性都受到氧气的抑制。一氧化碳不抑制线粒体Nfx硝基还原酶，仅抑制10%的微粒体酶活性。次黄嘌呤依赖性胞质活性受到别嘌呤醇的抑制。目前的结果表明，Nfx通过大鼠肾上腺细胞器中的硝基还原生物转化被激活，产生具有损伤作用的活性代谢物。线粒体和微粒体的生物激活将发生在黄素酶P-450还原酶水平，而不是P-450本身，胞质生物激活将由黄嘌呤氧化酶介导。有必要对接受Nfx治疗的患者的肾上腺功能进行流行病学研究，以确定这些发现的潜在毒理学相关性。
