Oxidative and Reductive Metabolism of Tris(p-carboxyltetrathiaaryl)methyl Radicals by Liver Microsomes

• Published in: Chemical research in toxicology 2009-07, Vol.22 (7), p.1342-1350
• Main Authors: Decroos, Christophe, Li, Yun, Bertho, Gildas, Frapart, Yves, Mansuy, Daniel, Boucher, Jean-Luc
• Format: Article
• Language: English
• Subjects: Animals; Chemical Sciences; Contrast Media - chemistry; Contrast Media - metabolism; Cytochrome P-450 Enzyme System - metabolism; Electron Spin Resonance Spectroscopy; Free Radicals - chemistry; Heterocyclic Compounds, 3-Ring - chemistry; Heterocyclic Compounds, 3-Ring - metabolism; Humans; Life Sciences; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; NADPH-Ferrihemoprotein Reductase - metabolism; Oxidation-Reduction; Rats; Spectrophotometry, Ultraviolet; Swine
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx9001379

Tris(p-carboxyltetrathiaaryl)methyl (TAM) radicals are particularly stable carbon-centered free radicals that are used as contrast agents in NMR imaging and as probes for in vivo oximetry by electron paramagnetic resonance (EPR) imaging. However, nothing is known so far on the metabolism of these persistent radicals in mammals. This article describes the metabolism of two TAM radicals by rat, human, and pig liver microsomes. It shows that microsomal transformation of these free radicals leads to two major metabolites resulting from an oxidation or a reduction of the present compounds. The structures of these metabolites were completely established by 1H and 13C NMR spectroscopy, mass spectrometry, and comparison with authentic compounds. Under aerobic conditions, liver microsomes catalyzed the oxidative decarboxylation of TAM radicals by NADPH and O2 with formation of the corresponding quinone-methide products. This reaction was dependent on cytochromes P450 and cytochrome P450 reductase and greatly implied the involvement of superoxide. Under anaerobic conditions, these enzymes catalyzed the reduction of TAM radicals to the corresponding triarylmethanes. This reduction was strongly inhibited by O2. These metabolic transformations should be considered when using such TAM radicals for pO2 measurement by EPR imaging, especially in tissues in which fast oxidative (inflammation sites) or reductive (hypoxic tissues) metabolism could occur.