Comparative Metabolism of 1,2,3,3,3-Pentafluoropropene in Male and Female Mouse, Rat, Dog, and Human Liver Microsomes and Cytosol and Male Rat Hepatocytes via Oxidative Dehalogenation and Glutathione S-Conjugation Pathways

Abstract

In vitro metabolism of 1,2,3,3,3-pentafluoropropene (PFP) was investigated in the present study. PFP was metabolized via cytochrome P450-catalyzed oxidative dehalogenation in liver microsomes and glutathione 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 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 K(m) values than rat, mouse, and human microsomes. Sex differences in the rates of metabolism within a given species were minor and generally were less than 2-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 approximately 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 of the 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 K(m) for TFPA).