Abraham R T, Knapp J E, Minnigh M B, Wong L K, Zemaitis M A, Alvin J D
Drug Metab Dispos. 1984 Nov-Dec;12(6):732-41.
The metabolism of furazolidone by rat liver and Escherichia coli was characterized in vitro under aerobic and anaerobic incubation conditions. Rat liver 9000g supernatant rapidly metabolized 14C-furazo-lidone to more polar metabolites in the presence or absence of oxygen when NADPH was provided as a cofactor. At least five polar radiolabeled metabolites were detected in these incubations by high pressure liquid chromatography. Moreover, a significant (30-40%) proportion of the total radiolabeled metabolites remained tightly associated with liver protein despite repeated organic solvent extractions of the tissue. The major solvent-extractable metabolites produced under aerobic and anaerobic incubation conditions were isolated and analyzed by mass spectrometry. The mass spectra indicated that these derivatives possessed the same chemical structure. Subsequently, this metabolite was unequivocally identified as 3-(4-cyano-2-oxobutylideneamino)-2-oxazolidinone, an end product of reductive metabolism of the nitro group of furazolidone. The formation of the reduced metabolite under aerobic conditions indicated that this metabolic pathway was markedly less sensitive to oxygen than many previously studied nitroreduction reactions catalyzed by mammalian enzymes. This NADPH-dependent, oxygen-insensitive nitroreductase activity was further localized to the microsomal fraction of rat liver. E. coli also rapidly metabolized furazolidone (FZN) to a complex series of metabolites, including the reduced cyano metabolite, under both aerobic and anaerobic conditions. Sonic lysis of the bacteria released an NADPH-dependent, oxygen-insensitive nitroreductase which converted FZN to the cyano metabolite and other unidentified derivatives. The complete reduction of FZN by the solubilized bacterial enzyme was strongly inhibited by the addition of the thiol nucleophile glutathione to the incubation medium.
在需氧和厌氧培养条件下，对大鼠肝脏和大肠杆菌中呋喃唑酮的代谢进行了体外研究。当提供NADPH作为辅助因子时，无论有无氧气，大鼠肝脏9000g上清液都能迅速将14C-呋喃唑酮代谢为极性更强的代谢产物。通过高压液相色谱法在这些培养物中检测到至少五种极性放射性标记代谢产物。此外，尽管对组织进行了多次有机溶剂萃取，但总放射性标记代谢产物中有相当大比例（30%-40%）仍与肝脏蛋白紧密结合。分离出在需氧和厌氧培养条件下产生的主要可被溶剂萃取的代谢产物，并通过质谱分析。质谱表明这些衍生物具有相同的化学结构。随后，该代谢产物被明确鉴定为3-(4-氰基-2-氧代丁烯基氨基)-2-恶唑烷酮，这是呋喃唑酮硝基还原代谢的终产物。在需氧条件下还原代谢产物的形成表明，该代谢途径对氧气的敏感性明显低于许多先前研究的由哺乳动物酶催化的硝基还原反应。这种依赖NADPH且对氧气不敏感的硝基还原酶活性进一步定位于大鼠肝脏的微粒体部分。在需氧和厌氧条件下，大肠杆菌也能迅速将呋喃唑酮（FZN）代谢为一系列复杂的代谢产物，包括还原的氰基代谢产物。细菌的超声裂解释放出一种依赖NADPH且对氧气不敏感的硝基还原酶，该酶将FZN转化为氰基代谢产物和其他未鉴定的衍生物。向孵育培养基中添加硫醇亲核试剂谷胱甘肽可强烈抑制溶解的细菌酶对FZN的完全还原。
