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Updated: May 24, 2026

An Integrated Raman Spectroscopy and Mass Spectrometry Platform to Study Single-Cell Drug Uptake, Metabolism, and Effects
Published on: January 9, 2020
Free radical metabolism of raloxifene in human liver microsomes
Heng-Keang Lim1, Min Yang, Wing Lam
1Drug Metabolism and Pharmacokinetics, Drug Safety Sciences, Janssen Research and Development, 1000 Route 202 South, Raritan, NJ 08869, USA. hlim5@its.jnj.com
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.
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