Free radical metabolism of raloxifene in human liver microsomes

Raloxifene was metabolized predominantly by CYP3A4 in human liver microsomes to a pair of carbon-carbon (RD1-2) and ether (RD3-4) linked homodimers in an nicotinamide adenine dinucleotide phosphate-dependent manner. The major homodimer formed by human liver microsomes (RD3) was different from the ma...

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Published in:Xenobiotica 2012-08, Vol.42 (8), p.737-747
Main Authors: Lim, Heng-Keang, Yang, Min, Lam, Wing, Xu, Fran, Chen, Jie, Xu, Yaodong, Shetty, H. Umesha, Yang, Ke, Silva, Jose, Evans, David C.
Format: Article
Language:English
Subjects:
Chromatography, Liquid
CYP3A4
Dimerization
Free Radicals - metabolism
H/D exchange
Homodimer
horseradish peroxidase
Humans
Magnetic Resonance Spectroscopy
Mass Spectrometry
Microsomes, Liver - metabolism
myeloperoxidase
Orbitrap
phenoxy radical
Raloxifene Hydrochloride - chemistry
Raloxifene Hydrochloride - metabolism
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Summary:Raloxifene was metabolized predominantly by CYP3A4 in human liver microsomes to a pair of carbon-carbon (RD1-2) and ether (RD3-4) linked homodimers in an nicotinamide adenine dinucleotide phosphate-dependent manner. The major homodimer formed by human liver microsomes (RD3) was different from the major homodimer formed by peroxidases (RD1). RD1, 3 and 4 were identified by both mass spectrometry (MS) and nuclear magnetic resonance (NMR) as symmetrical carbon-carbon (both carbon 7 from benzo[b]thiopen-6-ol) linked homodimer, asymmetrical ether (oxygen from 4-hydroxyphenyl and carbon 7 from benzo[b]thiopen-6-ol) linked homodimer and asymmetrical ether (oxygen and carbon 7 from benzo[b]thiopen-6-ol) linked homodimer, respectively. The structures of the homodimers RD1, 3 and 4 provided evidence for free radical metabolism of raloxifene by predominantly CYP3A4 in human liver microsomes to oxygen-centered phenoxy radicals from 4-hydroxyphenyl and benzo[b]thiopen-6-ol moieties. Further delocalization to ortho carbon-centered radical was only observed for benzo[b]thiopen-6-ol derived phenoxy radical.
ISSN:0049-8254
1366-5928
DOI:10.3109/00498254.2012.662306