ACETAMINOPHEN ACTIVATION BY HUMAN-LIVER CYTOCHROMES P450IIE1 AND P450IA2
ACETAMINOPHEN ACTIVATION BY HUMAN-LIVER CYTOCHROMES P450IIE1 AND P450IA2
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DOI：
10.1016/0003-9861(89)90278-6
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发表时间：
1989-06-01
影响因子：
3.9
通讯作者：
BLACK, M
中科院分区：
文献类型：
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作者：
RAUCY, JL;LASKER, JM;BLACK, M
对乙酰氨基酚（APAP）是一种广泛使用的非处方镇痛药，已知在动物和人类中大量摄入时会引起肝毒性，特别是在慢性乙醇消耗后给药时。肝毒性源于微粒体P450单加氧酶将APAP活化为与组织大分子结合的反应性代谢物，从而引发细胞坏死。饮酒还导致P450 IIE 1的诱导，P450 IIE 1是一种肝微粒体酶，在重建研究中已被证明是APAP氧化的有效催化剂。因此，微粒体P450 IIE 1水平升高不仅可以解释已知的增加APAP生物活化活性的肝微粒体后，长期乙醇摄入，但也增强了敏感性APAP毒性。因此，我们研究了P450 IIE 1在人肝微粒体APAP激活中的作用。我们的研究结果表明，两个P450同工酶，即P450 IIE 1和P450 IA 2，催化几乎所有的APAP激活在人肝微粒体。由于APAP的生物活化被认为介导其毒性，那么影响P450 IIE 1的肝脏水平的那些因素（例如，慢性酒精消耗）和/或P450 IA 2可能显著影响某些个体对APAP促进的肝损伤的易感性。
Acetaminophen (APAP), a widely used over-the-counter analgesic, is known to cause hepatotoxicity when ingested in large quantities in both animals and man, especially when administered after chronic ethanol consumption. Hepatotoxicity stems from APAP activation by microsomal P450 monooxygenases to a reactive metabolite that binds to tissue macromolecules, thereby initiating cellular necrosis. Alcohol consumption also causes the induction of P450IIE1, a liver microsomal enzyme that in reconstitution studies has proven to be an effective catalyst of APAP oxidation. Thus, elevated microsomal P450IIE1 levels could explain not only the kknown increase in APAP bioactivating activity of liver microsomes after prolonged ethanol ingestion but also the enhanced susceptibility to APAP toxicity. We therefore examined the role of P450IIE1 in human liver microsomal APAP activation. Our results indicate that two P450 isozymes, namely P450IIE1 and P450IA2, catalyze nearly all of the APAP activation in human liver microsomes. Since bioactivation of APAP is presumed to mediate its toxicity, then those factors affecting the hepatic levels of P450IIE1 (e.g., chronic alcohol consumption) and/or P450IA2 may markedly influence the susceptibility of certain individuals to APAP-promoted liver damage.