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Metabolism of melatonin by cytochrome P450s in rat liver mitochondria and microsomes.
Journal of Pineal Research ( IF 10.3 ) Pub Date : 2008-08-19 , DOI: 10.1111/j.1600-079x.2008.00630.x
Igor Semak 1 , Elena Korik , Maria Antonova , Jacobo Wortsman , Andrzej Slominski
Affiliation  

In the present study we provide direct evidence for the involvement of rat microsomal cytochrome P450s in melatonin O-demethylation and hydroxylation at two different positions: 2 and 6, as well as generation of N(1)-acetyl-N(2)-formyl-5-methoxy-kynuramine (AFMK) and two unknown products. Moreover, we found that mitochondrial cytochrome P450s also converts melatonin into AFMK, N-acetylserotonin, 2-hydroxymelatonin, 6-hydroxymelatonin and the same two unknown products. Eadie-Hofstee plots for 6-hydroxylation and O-demethylation reactions were curvilinear for all tested fractions, suggestive of involvement of at least two components, one with a high affinity and low capacity, and another with a low affinity and high capacity. Mitochondrial cytochrome P450s exhibited higher affinity (suggesting lower K(m) value) and higher V(max) for melatonin 6-hydroxylation and O-demethylation for both high-affinity and low-affinity components as compared with microsomal enzymes. The intrinsic clearance for melatonin hydroxylation by high- and low-affinity components displayed the highest values in all tested fractions, indicating that both mitochondrial and microsomal cytochrome P450s metabolize melatonin principally by 6-hydroxylation, with O-demethylation representing a minor metabolic pathway.

中文翻译:

大鼠肝脏线粒体和微粒体中细胞色素 P450 对褪黑激素的代谢。

在本研究中,我们提供了大鼠微粒体细胞色素 P450 在两个不同位置参与褪黑激素 O-去甲基化和羟基化的直接证据:2 和 6,以及 N(1)-乙酰基-N(2)-甲酰基的生成-5-甲氧基犬尿胺 (AFMK) 和两种未知产品。此外,我们发现线粒体细胞色素 P450s 也将褪黑激素转化为 AFMK、N-乙酰5-羟色胺、2-羟基褪黑激素、6-羟基褪黑激素和相同的两种未知产物。6-羟基化和 O-去甲基化反应的 Eadie-Hofstee 图对于所有测试级分都是曲线的,表明至少涉及两种组分,一种具有高亲和力和低容量,另一种具有低亲和力和高容量。与微粒体酶相比,线粒体细胞色素 P450s 表现出更高的亲和力(表明较低的 K(m) 值)和较高的 V(max) 褪黑激素 6-羟基化和 O-去甲基化的高亲和力和低亲和力成分。高亲和力和低亲和力成分对褪黑激素羟基化的内在清除率在所有测试组分中显示出最高值,表明线粒体和微粒体细胞色素 P450 主要通过 6-羟基化代谢褪黑激素,其中 O-去甲基化代表次要代谢途径。
更新日期:2019-11-01
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