Schut H A, Dixit R, Loeb T R, Stoner G D
Biochem Pharmacol. 1985 Apr 1;34(7):969-76. doi: 10.1016/0006-2952(85)90598-2.
The elimination and metabolism of a single dose (100 mg/kg) of 2,4-dinitrotoluene (2,4-DNT) in A/J mice were examined. After intraperitoneal administration, elimination was rapid, with 70% of the dose appearing in the urine within 4 hr. Four hours after oral administration, only 28.5% of the dose was excreted in the urine, which increased to 66% after 8 hr. Elimination via the feces was minimal (less than 2.1% of the dose) in both cases. From 0.5 to 4 hr after intraperitoneal administration, 3.6 to 8.8% of the urinary metabolites was unconjugated while 2.4 to 8.8% was present in the glucuronide fraction. After oral administration these amounts were 5.5 to 6.8% and 20.5 to 28.2% respectively. After both intraperitoneal and oral administration, no unchanged 2,4-DNT could be detected in the urine, and 2,4-dinitrobenzyl alcohol (2,4-DNBAlc) represented the most abundant identifiable neutral metabolite. Small amounts of 2,4-diaminotoluene, 2-amino-4-nitrobenzyl alcohol, 2-(N-acetyl)amino-4-nitrotoluene, 4-amino-2-nitrotoluene (4A2NT), and 2-amino-4-nitrotoluene (2A4NT) were also present. In almost all cases the largest proportion of metabolites represented unknowns, some of which exhibited the chromatographic properties of carboxylic acid metabolites. Metabolism of 2,4-DNT by liver and lung microsomes yielded mainly 2,4-DNBAlc with lower amounts of 4A2NT and 2A4NT, and their formation was dependent on the presence of oxygen and NADPH. Pretreatment of the animals with 2,3,7,8-tetrachlorodibenzo-p-dioxin resulted in increased yields of all three metabolites. Aerobic metabolism of 2,4-DNT by explants of the small intestine, large intestine, or by cecal contents yielded 2,4-DNBAlc, 2A4NT, 4A2NT and 4-(N-acetyl)amino-2-nitrotoluene (4Ac2NT). The proportion of reduced metabolites (2A4NT, 4A2NT, and 4Ac2NT) was much higher in these systems than with liver or lung microsomes and their formation by small intestine and cecal contents was enhanced several-fold under anaerobic conditions, while that of 2,4-DNBAlc was abolished. It is concluded that 2,4-DNT metabolism in the A/J mouse is rapid and complete and that the major neutral urinary metabolite is 2,4-DNBAlc. Minor amounts of reduced or partially reduced products appear to be formed mainly in the intestine, with a major role by its microflora.
研究了单剂量（100mg/kg）2,4-二硝基甲苯（2,4-DNT）在A/J小鼠体内的消除和代谢情况。腹腔注射后，消除迅速，4小时内70%的剂量出现在尿液中。口服给药4小时后，仅28.5%的剂量经尿液排出，8小时后增至66%。两种给药方式下，经粪便的消除量均极少（小于剂量的2.1%）。腹腔注射后0.5至4小时，尿液代谢物中3.6%至8.8%为未结合形式，2.4%至8.8%存在于葡萄糖醛酸苷部分。口服给药后，这些量分别为5.5%至6.8%和20.5%至28.2%。腹腔注射和口服给药后，尿液中均未检测到未代谢的2,4-DNT，2,4-二硝基苄醇（2,4-DNBAlc）是最主要的可鉴定中性代谢物。还存在少量的2,4-二氨基甲苯、2-氨基-4-硝基苄醇、2-（N-乙酰基）氨基-4-硝基甲苯、4-氨基-2-硝基甲苯（4A2NT）和2-氨基-4-硝基甲苯（2A4NT）。几乎在所有情况下，代谢物的最大比例为未知物，其中一些具有羧酸代谢物的色谱特性。肝脏和肺微粒体对2,4-DNT的代谢主要产生2,4-DNBAlc，4A2NT和2A4NT的量较少，其形成依赖于氧气和NADPH的存在。用2,3,7,8-四氯二苯并对二恶英预处理动物会导致所有三种代谢物的产量增加。小肠、大肠外植体或盲肠内容物对2,4-DNT的需氧代谢产生2,4-DNBAlc、2A4NT、4A2NT和4-（N-乙酰基）氨基-2-硝基甲苯（4Ac2NT）。这些系统中还原代谢物（2A4NT、4A2NT和4Ac2NT）的比例远高于肝脏或肺微粒体，小肠和盲肠内容物在厌氧条件下形成的还原代谢物增加了几倍，而2,4-DNBAlc的形成则被消除。结论是，A/J小鼠体内2,4-DNT的代谢迅速且完全，主要的中性尿液代谢物是2,4-DNBAlc。少量还原或部分还原产物似乎主要在肠道中形成，其微生物群起主要作用。
