title: Free radical metabolism of raloxifene in human liver microsomes.
abstract: 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.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Drug Safety Sciences, Janssen Research and Development, 1000 Route 202 South, Raritan, NJ 08869, USA. hlim5@its.jnj.com
authors.forename: Heng-Keang
authors.initials: HK
authors.lastname: Lim
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Wing
authors.initials: W
authors.lastname: Lam
authors.forename: Fran
authors.initials: F
authors.lastname: Xu
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Yaodong
authors.initials: Y
authors.lastname: Xu
authors.forename: H Umesha
authors.initials: HU
authors.lastname: Shetty
authors.forename: Ke
authors.initials: K
authors.lastname: Yang
authors.forename: Jose
authors.initials: J
authors.lastname: Silva
authors.forename: David C
authors.initials: DC
authors.lastname: Evans
mesh_terms: D002853:Chromatography, Liquid; D019281:Dimerization; D005609:Free Radicals / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism*; D020849:Raloxifene Hydrochloride / Q000737:chemistry / Q000378:metabolism*; D013113:Spin Labels
chemical_list: D005609:Free Radicals; D013113:Spin Labels; D020849:Raloxifene Hydrochloride