title: Disruption of mitochondrial activities in rabbit and human hepatocytes by a quinoxalinone anxiolytic and its carboxylic acid metabolite.
abstract: The quinoxalinone anxiolytic, panadiplon, was dropped from clinical development due to unexpected hepatic toxicity in human volunteers. Subsequent experimental studies in rabbits demonstrated a hepatic toxicity that resembled Reye's syndrome. In the present studies, we examined the effects of panadiplon and a metabolite, cyclopropane carboxylic acid (CPCA) on hepatic mitochondrial activities in vitro and ex vivo. Acute inhibition of beta-oidation of [14C]palmitate was observed in rabbit and human hepatocyte suspensions incubated with 100 microM panadiplon. Panadiplon (30 microM) also reduced mitochondrial uptake of rhodamine 123 (R123) in cultured rabbit and human, but not rat hepatocytes, following 18 h exposure. CPCA also impaired beta-oxidation and R123 uptake in rabbit and human hepatocytes. R123 uptake and beta-oxidation in cells from some donors was not impaired by either agent, and cell death was not observed in any experiment. Hepatocytes isolated from panadiplon-treated rabbits had reduced palmitate beta-oxidation rates and inhibited mitochondrial R123 uptake; R123 uptake remained inhibited until 48-72 h in culture. Rabbit mitochondrial respiration experiments revealed a slightly lower ratio of ATP formed/oxygen consumed in panadiplon-treated animals: direct exposure of normal rabbit liver mitochondria to panadiplon did not have this effect. Hepatocytes isolated from panadiplon-treated rabbits showed reduced respiratory control ratios and lower oxygen consumption compared to controls. Our results indicate that panadiplon induces a mitochondrial dysfunction in the liver, and suggest that this dysfunction may be attributed to the carboxylic acid metabolite.
authors.affiliation: Pharmacia and Upjohn, Inc., Kalamazoo, MI 49007, USA. roger.ulrich@abbott.com
authors.forename: R G
authors.initials: RG
authors.lastname: Ulrich
authors.forename: J A
authors.initials: JA
authors.lastname: Bacon
authors.forename: C T
authors.initials: CT
authors.lastname: Cramer
authors.forename: D K
authors.initials: DK
authors.lastname: Petrella
authors.forename: E L
authors.initials: EL
authors.lastname: Sun
authors.forename: M D
authors.initials: MD
authors.lastname: Meglasson
authors.forename: E
authors.initials: E
authors.lastname: Holmuhamedov
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D014151:Anti-Anxiety Agents / Q000633:toxicity*; D019069:Cell Respiration / Q000187:drug effects; D002478:Cells, Cultured; D002675:Child, Preschool; D003521:Cyclopropanes / Q000633:toxicity*; D005260:Female; D005456:Fluorescent Dyes; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000187:drug effects*; D010069:Oxadiazoles / Q000633:toxicity*; D010084:Oxidation-Reduction; D011810:Quinoxalines / Q000633:toxicity*; D011817:Rabbits; D051381:Rats; D020112:Rhodamine 123; D013045:Species Specificity
chemical_list: D014151:Anti-Anxiety Agents; D003521:Cyclopropanes; D005456:Fluorescent Dyes; D010069:Oxadiazoles; D011810:Quinoxalines; C015766:cyclopropanecarboxylic acid; D020112:Rhodamine 123; C069443:panadiplon