Metabolism of melatonin by cytochrome P450s in rat liver mitochondria and microsomes
Version of Record online: 20 AUG 2008
© 2008 The Authors. Journal compilation © 2008 Blackwell Munksgaard
Journal of Pineal Research
Volume 45, Issue 4, pages 515–523, November 2008
How to Cite
Semak, I., Korik, E., Antonova, M., Wortsman, J. and Slominski, A. (2008), Metabolism of melatonin by cytochrome P450s in rat liver mitochondria and microsomes. Journal of Pineal Research, 45: 515–523. doi: 10.1111/j.1600-079X.2008.00630.x
- Issue online: 9 OCT 2008
- Version of Record online: 20 AUG 2008
- Received April 16, 2008; accepted July 22, 2008.
- cytochrome P450;
- N1-acetyl-N 2-formyl-5-methoxy-kynuramine;
Abstract: 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 N1-acetyl-N2-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 Km value) and higher Vmax 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.