Inhibition of acetaminophen sulfation by 2,6-dichloro-4-nitrophenol in the perfused rat liver preparation. Lack of a compensatory increase of glucuronidation.
Inhibition of acetaminophen sulfation by 2,6-dichloro-4-nitrophenol in the perfused rat liver preparation. Lack of a compensatory increase of glucuronidation.
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2,6-二氯-4-硝基苯酚在灌注大鼠肝脏制剂中抑制对乙酰氨基酚硫酸化。
DOI：
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发表时间：
1984
影响因子：
3.9
通讯作者：
K. Pang
中科院分区：
文献类型：
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作者：
S. Fayz;W. Cherry;J. Dawson;G. Mulder;K. Pang
在一次性灌注大鼠肝脏制剂中研究了 2,6-二氯-4-硝基苯酚 ( DCNP ) 作为对乙酰氨基酚硫酸化抑制剂的有效性，以及 DCNP 对其他结合反应（如葡萄糖醛酸化和谷胱甘肽结合）的影响。当由于不存在无机硫酸盐或存在 DCNP 而抑制硫酸化时，对乙酰氨基酚的葡萄糖醛酸和谷胱甘肽缀合物的形成是微不足道的，这表明对乙酰氨基酚是葡萄糖醛酸化（高 Km）和反应性代谢物形成的不良底物，从而导致对乙酰氨基酚谷胱甘肽缀合物的形成。在低浓度的对乙酰氨基酚下，DCNP 在抑制硫酸化方面最有效，并且抑制程度随着 DCNP 浓度的增加而增加，这可能是由于竞争性抑制机制。随后对 3H-对乙酰氨基酚和 40 microM DCNP 示踪剂浓度的研究表明，在 DCNP 存在下，对乙酰氨基酚的稳态肝提取率降低了 16%，硫酸化降低了 19%，而葡萄糖醛酸化增加了 28%；谷胱甘肽结合不受影响。由于对乙酰氨基酚是葡萄糖醛酸化的不良底物，并且葡萄糖醛酸化仍然是对乙酰氨基酚生物转化中的次要代谢途径，因此 DCNP 对对乙酰氨基酚的葡萄糖醛酸化的变化（比对照值高 28%）未能影响对乙酰氨基酚处置的总体变化。相反，DCNP 抑制对乙酰氨基酚硫酸化是导致对乙酰氨基酚肝提取减少的原因。 DCNP 对对乙酰氨基酚硫酸化的这种抑制很容易可逆。
The effectiveness of 2,6-dichloro-4-nitrophenol ( DCNP ) as an inhibitor of sulfation of acetaminophen, and the effect of DCNP on other conjugation reactions such as glucuronidation and glutathione conjugation were investigated in the once-through perfused rat liver preparation. The formation of glucuronide and glutathione conjugates of acetaminophen was insignificant under conditions when sulfation was suppressed either by the absence of inorganic sulfate or the presence of DCNP , suggesting that acetaminophen was a poor substrate for glucuronidation (high Km) and for the formation of the reactive metabolite leading to the formation of acetaminophen glutathione conjugate. DCNP was most effective in suppressing sulfation at low concentrations of acetaminophen, and the degree of inhibition increased with DCNP concentration, possibly due to a competitive mechanism of inhibition. Subsequent studies with tracer concentration of 3H-acetaminophen and 40 microM DCNP indicated that the steady state hepatic extraction ratio of acetaminophen decreased by 16%, sulfation was reduced by 19%, whereas glucuronidation increased by 28% in the presence of DCNP ; glutathione conjugation was not affected. Because acetaminophen is a poor substrate for glucuronidation and because glucuronidation remains a minor metabolic pathway in the biotransformation of acetaminophen, the changes in glucuronidation of acetaminophen with DCNP (28% above control value) failed to effect gross changes in acetaminophen disposition. Rather, the suppression of acetaminophen sulfation by DCNP is responsible for the decreased hepatic extraction of acetaminophen. This inhibition of acetaminophen sulfation by DCNP is readily reversible.