Deficiency of N-acetyltransferase increases the interactions of isoniazid with endobiotics in mouse liver.
Deficiency of N-acetyltransferase increases the interactions of isoniazid with endobiotics in mouse liver.
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DOI：
10.1016/j.bcp.2017.09.001
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发表时间：
2017-12-01
影响因子：
5.8
通讯作者：
Ma X
中科院分区：
文献类型：
--
作者：
Wang P;Shehu AI;Lu J;Joshi RH;Venkataramanan R;Sugamori KS;Grant DM;Zhong XB;Ma X
乙酰化是异烟肼（INH）的主要代谢途径，由N-乙酰转移酶（NATs）介导。以往的研究表明，慢乙酰化剂比快乙酰化剂具有更高的INH肝毒性风险，但详细的机制仍不清楚。目前的研究使用Nat 1/2（−/−）小鼠来模拟NAT慢代谢者，并研究肝脏中的INH代谢。我们发现，在Nat 1/2（−/−）小鼠的肝脏中，INH乙酰化被消除，这表明INH乙酰化完全依赖于Nat 1/2。除乙酰化途径外，INH还可水解形成肼（Hz）和异烟酸（INA）。我们发现Nat 1/2（−/−）小鼠肝脏中的INA水平没有改变，表明Nat 1/2缺乏对INH水解没有影响。因为在Nat 1/2（−/−）小鼠中INH乙酰化被消除，而INH水解没有改变，我们预期肝脏中的INH水平极高。然而，我们仅观察到在Nat 1/2（−/−）小鼠的肝脏中INH的适度积累，这表明在Nat 1/2缺陷条件下INH代谢存在替代途径。我们进一步的研究表明，INH与内生菌的结合代谢物，包括脂肪酸和维生素B6，在Nat 1/2（−/−）小鼠的肝脏中显着增加。总之，这项研究表明，缺乏NAT 1/2降低INH乙酰化，但增加了INH与肝脏内生物的相互作用。这些发现可以用来指导未来的研究在NAT慢代谢者的INH肝毒性的机制。
Acetylation is the major metabolic pathway of isoniazid (INH) mediated by N-acetyltransferases (NATs). Previous reports suggest that slow acetylators have higher risks of INH hepatotoxicity than rapid acetylators, but the detailed mechanisms remain elusive. The current study used Nat1/2(−/−) mice to mimic NAT slow metabolizers and to investigate INH metabolism in the liver. We found that INH acetylation is abolished in the liver of Nat1/2(−/−) mice, suggesting that INH acetylation is fully dependent on NAT1/2. In addition to the acetylation pathway, INH can be hydrolyzed to form hydrazine (Hz) and isonicotinic acid (INA). We found that INA level was not altered in the liver of Nat1/2(−/−) mice, indicating that deficiency of NAT1/2 has no effect on INH hydrolysis. Because INH acetylation was abolished and INH hydrolysis was not altered in Nat1/2(−/−) mice, we expected an extremely high level of INH in the liver. However, we only observed a modest accumulation of INH in the liver of Nat1/2(−/−) mice, suggesting that there are alternative pathways in INH metabolism in NAT1/2 deficient condition. Our further studies revealed that the conjugated metabolites of INH with endobiotics, including fatty acids and vitamin B6, were significantly increased in the liver of Nat1/2(−/−) mice. In summary, this study illustrated that deficiency of NAT1/2 decreases INH acetylation, but increases the interactions of INH with endobiotics in the liver. These findings can be used to guide future studies on the mechanisms of INH hepatotoxicity in NAT slow metabolizers.
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