Henderson Marilyn C, Siddens Lisbeth K, Morré Jeffrey T, Krueger Sharon K, Williams David E
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331-7301, USA.
Toxicol Appl Pharmacol. 2008 Dec 15;233(3):420-7. doi: 10.1016/j.taap.2008.09.017. Epub 2008 Oct 1.
Tuberculosis (TB) results from infection with Mycobacterium tuberculosis and remains endemic throughout the world with one-third of the world's population infected. The prevalence of multi-drug resistant strains necessitates the use of more toxic second-line drugs such as ethionamide (ETA), a pro-drug requiring bioactivation to exert toxicity. M. tuberculosis possesses a flavin monooxygenase (EtaA) that oxygenates ETA first to the sulfoxide and then to 2-ethyl-4-amidopyridine, presumably through a second oxygenation involving sulfinic acid. ETA is also a substrate for mammalian flavin-containing monooxygenases (FMOs). We examined activity of expressed human and mouse FMOs toward ETA, as well as liver and lung microsomes. All FMOs converted ETA to the S-oxide (ETASO), the first step in bioactivation. Compared to M. tuberculosis, the second S-oxygenation to the sulfinic acid is slow. Mouse liver and lung microsomes, as well as human lung microsomes from an individual expressing active FMO, oxygenated ETA in the same manner as expressed FMOs, confirming this reaction functions in the major target organs for therapeutics (lung) and toxicity (liver). Inhibition by thiourea, and lack of inhibition by SKF-525A, confirm ETASO formation is primarily via FMO, particularly in lung. ETASO production was attenuated in a concentration-dependent manner by glutathione. FMO3 in human liver may contribute to the toxicity and/or affect efficacy of ETA administration. Additionally, there may be therapeutic implications of efficacy and toxicity in human lung based on the FMO2 genetic polymorphism, though further studies are needed to confirm that suggestion.
结核病（TB）由结核分枝杆菌感染引起，在全球范围内仍然流行，全球三分之一的人口受到感染。多重耐药菌株的流行使得必须使用毒性更强的二线药物，如乙硫异烟胺（ETA），这是一种前体药物，需要生物活化才能发挥毒性。结核分枝杆菌拥有一种黄素单加氧酶（EtaA），它首先将ETA氧化为亚砜，然后氧化为2-乙基-4-氨基吡啶，推测是通过涉及亚磺酸的第二次氧化作用。ETA也是哺乳动物含黄素单加氧酶（FMOs）的底物。我们研究了表达的人和小鼠FMOs对ETA的活性，以及肝脏和肺微粒体的活性。所有FMOs都将ETA转化为S-氧化物（ETASO），这是生物活化的第一步。与结核分枝杆菌相比，向亚磺酸的第二次S-氧化作用较慢。小鼠肝脏和肺微粒体，以及来自表达活性FMO的个体的人肺微粒体，以与表达的FMOs相同的方式氧化ETA，证实了该反应在治疗的主要靶器官（肺）和毒性靶器官（肝脏）中起作用。硫脲的抑制作用以及SKF-525A缺乏抑制作用，证实ETASO的形成主要通过FMO，特别是在肺中。谷胱甘肽以浓度依赖的方式减弱了ETASO的产生。人肝脏中的FMO3可能导致ETA给药的毒性和/或影响其疗效。此外，基于FMO2基因多态性，人肺中的疗效和毒性可能具有治疗意义，不过需要进一步研究来证实这一推测。
