TY - JOUR T1 - Comparative Metabolism of 1,2,3,3,3-Pentafluoropropene in Male and Female Mouse, Rat, Dog, and Human Liver Microsomes and Cytosol and in Male Rat Hepatocytes Via Oxidative Dehalogenation and Glutathione S-Conjugation Pathways JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.111.038299 SP - dmd.111.038299 AU - Xing Han AU - Bogdan Szostek AU - Ching-Hui Yang AU - Steve Cheatham AU - Robert Mingoia AU - Diane Nabb AU - Shawn Gannon AU - Matthew Himmelstein AU - Gary Jepson Y1 - 2011/01/01 UR - http://dmd.aspetjournals.org/content/early/2011/04/14/dmd.111.038299.abstract N2 - In vitro metabolism of 1,2,3,3,3-pentafluoropropene (PFP) is investigated in the present study. PFP was metabolized via cytochrome P450-catalyzed oxidative dehalogenation in liver microsomes and glutathione S-transferase (GST)-catalyzed conjugation in liver microsomes and cytosol. Two oxidation products, 2,3,3,3-tetrafluoropropionaldehyde (TPA) and 3,3,3-trifluoropyruvaldehyde (TFPA), and two glutathione (GSH) conjugates, S-(2,3,3,3-tetrafluoropropenyl)-GSH (TFPG) and S-(1,2,3,3,3-pentafluoropropyl)-GSH (PFPG) were identified. Enzyme kinetic parameters for the formation of TFPA, TFPG, and PFPG were obtained in male and female rat, mouse, dog, and human liver microsomes and cytosol, and were confirmed using freshly isolated male rat hepatocytes. For the TFPA pathway, dog microsomes exhibited much larger Km values than rat, mouse, and human microsomes. Sex differences in the rates of metabolism within a given species were minor and generally less than two-fold. Across the species, liver microsomes were the primary subcellular fraction for GSH S-conjugation and the apparent reaction rates for the formation of TFPG were much greater than those for PFPG in liver microsomes. PFPG was unstable and had a half-life of about 3.9 h in a phosphate buffer (pH 7.4 and 37 °C). The intrinsic clearance values for the formation of TFPA were much greater than those for the formation of GSH S-conjugates, suggesting that cytochrome P450-mediated oxidation is the primary pathway for the metabolism of PFP at relatively low PFP concentrations. Because saturation for GST-mediated reactions was not reached at the highest possible PFP concentration, GSH S-conjugation may become a much more important pathway at higher PFP concentrations (relative to the Km for TFPA). ER -