Document XRp9ZkkDzajYJbO8dVVDp6MBR

AR126-0161 SUMMARY OF THE EFFECTS OF PFC's ON MITOCHONDRIAL BIOENERGETICS IN VITRO The attached diagram describes the metabolic relationship for the various PFC's that were selected for inclusion in this study. The metabolic chart is adapted from the original as provided by Dr. Steve Gordon. Included in the diagram is a summary description of the biological activity of each metabolite, the details of which are described in the appended report and supplement. The identities of all test compounds were withheld from the person who performed the bioenergetic analyses (Dr. Anatoli Starkov) and the following legend reveals the code to the test compounds as referred to in the research report. PF10 PF10H PF12L PF12M PF95 PFO5SM PF143 SAL FC10 the acetic acid of FC10 FX12-linear FX12-mixed linear and branched FC95 the sulfonamide of FC95 (N-de-ethylated FX12) FC143 salicylic acid included as a positive control To briefly summarize, we found that FC95 and FC143 were weak inhibitors of mitochondrial bioenergetics in vitro. They would have to bioaccumulate to substantial levels to pose a significant concern in vivo. On the other hand, FX12 (both linear and mixed) and FC10 and its carboxylic acid metabolite (PF10H) werefar more potent. The IC50 for the protonophoric uncoupling of mitochondrial respiration by FXI2 (ca, 6 iM) compares to that of the classic uncoupler 24dinitrophenol (DNP). Whether safety concerns are warranted depends on if these metabolites are stable and if they bioaccumulate to sufficient concentrations during the course of chronic exposures. 04191 Our greatest concern is for the sulfonamide (PF95M), which is 5-fold more potent than DNP as an uncoupler of mitochondrial oxidative phosphorylation. The. 1C50 for the sulfonamide is approximately 15 uM, which compares with that of the most potent mitochondrial uncouplers known. It is highly reasonable to suspect that exposures to the sulfonamide, or its generation in vivo from an N-substituted precursor metabolite, may be associated with demonstrable symptoms attributable to the uncoupling of mitochondrial respiration. This concer is compounded by the rapid N-de-ethylation of FX12 in vivo and bioconcentration of the sulfonamide in liver". Since this metabolite has been detected in sera from both rats and humans', an aggressive kinetic characterization seems warranted. We suggest that future research focus on the sulfonamide. "Johnson, .D. and Ober, R.D. (1979) Study No. 137-093, International Research and Development Corporation, "Ma0nBriuckner.... Mispagel, M5. ad Bowen, IM. (190) Drug Met. Dispos 19: 205211. *Anon (1979). Tech. Report No., 723, 3M Central Analytical Laboratory, St. Paul, MN. 04192 | ie | CaFFi sorNsSopcnyCcoroe n es nc ripoveproto@6n04sM J J | N carrsorNgCHyCH3. carysonS (gSycnt Songo, tpronondnasNpphrhosNrearunocumpller e@6 64uM. stoan,cnmparrnodssp8e6r1mMet 0 | CoisrSoOPH, cFsroo coon en S TSa CTpHyi5sCO0H Fis deo st fort tsi Cai7s03 2<g skii nmrecns0y b1r0Mane &