Effects of dimethylsulfoxide on metabolism and toxicity of acetaminophen in mice.
Effects of dimethylsulfoxide on metabolism and toxicity of acetaminophen in mice.
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二甲亚砜对小鼠体内对乙酰氨基酚代谢和毒性的影响。
DOI：
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发表时间：
2006
影响因子：
2
通讯作者：
Y. Kim
中科院分区：
文献类型：
--
作者：
M. Yoon;Sun Ju Kim;Byung;J. Chung;Y. Kim
用雄性小鼠研究了二甲基亚砜（DMSO）对对乙酰氨基酚（APAP）代谢和毒性的影响。一剂量DMSO （1ml /kg, i.p.）几乎完全抑制APAP肝毒性的诱导，如血清肝毒性参数的变化所示。定量测定血浆中APAP的主要代谢物显示，DMSO预处理小鼠血浆中通过APAP代谢激活产生的偶联物APAP-谷胱甘肽（GSH）显著减少，而直接由母体药物产生的解毒代谢物APAP-硫酸盐和APAP-葡萄糖醛酸盐均增加。然而，以对硝基酚和对硝基苯甲醚为底物测量的微粒体CYP2E1活性在DMSO处理下增加。对照组小鼠微粒体中APAP-GSH的产生受DMSO的剂量依赖性抑制。Lineweaver-Burk图分析表明，DMSO产生的抑制模式本质上是竞争性的。用DMSO或盐处理动物的细胞质部分和微粒体重组10000 g上清。当使用盐处理小鼠的细胞质部分和/或dmso处理小鼠的微粒体时，APAP-GSH的产生显著增加。结果表明，DMSO诱导了APAP氧化代谢酶的活性，但其对APAP与酶相互作用的直接抑制作用减少了反应性代谢物的总体产生，从而降低了肝毒性。这表明，DMSO对异种生物代谢的影响取决于其抑制酶与异种生物相互作用的潜力。
Effects of dimethylsulfoxide (DMSO) on metabolism and toxicity of acetaminophen (APAP) were examined using male mice. A dose of DMSO (1 ml/kg, i.p.) inhibited the induction of APAP hepatotoxicity almost completely as indicated by changes in serum hepatotoxic parameters. Quantification of major APAP metabolites in plasma showed that APAP-glutathione (GSH), a conjugate generated via metabolic activation of APAP, was reduced significantly while APAP-sulfate and APAP-glucuronide, detoxified metabolites both produced directly from the parent drug, were increased in mice pretreated with DMSO. However, microsomal CYP2E1 activity measured with p-nitrophenol and p-nitroanisole as substrates was increased by DMSO treatment. Generation of APAP-GSH in microsomes from control mice was inhibited by DMSO in a dose-dependent manner. Lineweaver-Burk plot analysis indicated that the inhibition pattern produced by DMSO was competitive in nature. A 10000 g supernatant was reconstituted with the cytosolic fraction and microsomes from DMSO- or saline-treated animals. APAP-GSH production was increased significantly when the cytosolic fraction from saline-treated mice and/or microsomes from DMSO-treated mice were used. The results indicate that DMSO induces the enzyme activity responsible for oxidative metabolism of APAP, but its direct inhibitory effect on the enzymatic interaction with this drug decreases the overall production of a reactive metabolite, resulting in reduction of the hepatotoxicity. It is suggested that DMSO effects on metabolism of a xenobiotic would vary depending on its potential to inhibit the interaction of enzyme(s) and the xenobiotic.
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DOI：
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发表时间：
1988
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
Z. Gregus;C. Madhu;C. Klaassen
通讯作者：
Z. Gregus;C. Madhu;C. Klaassen
从乙醇处理的兔子的肝微粒体中分离出的细胞色素 P-450 同工酶 3a 的催化活性。
DOI：
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发表时间：
1982
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Morgan,ET;Koop,DR;Coon,MJ
通讯作者：
Coon,MJ
影响因子：
4.5
作者：
Youngja Park;Robin D. Smith;Alan B. Combs;James P. Kehrer
通讯作者：
Youngja Park;Robin D. Smith;Alan B. Combs;James P. Kehrer
影响因子：
3.9
作者：
RAUCY, JL;LASKER, JM;BLACK, M
通讯作者：
BLACK, M
影响因子：
3.6
作者：
D. Koop
通讯作者：
D. Koop