title: Reactivity of atropaldehyde, a felbamate metabolite in human liver tissue in vitro.
abstract: Antiepileptic therapy with a broad spectrum drug felbamate (FBM) has been limited due to reports of hepatotoxicity and aplastic anemia associated with its use. It was proposed that a bioactivation of FBM leading to formation of alpha,beta-unsaturated aldehyde, atropaldehyde (ATPAL) could be responsible for toxicities associated with the parent drug. Other members of this class of compounds, acrolein and 4-hydroxynonenal (HNE), are known for their reactivity and toxicity. It has been proposed that the bioactivation of FBM to ATPAL proceeds though a more stable cyclized product, 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one (CCMF) whose formation has been shown recently. Aldehyde dehydrogenase (ALDH) and glutathione transferase (GST) are detoxifying enzymes and targets for reactive aldehydes. This study examined effects of ATPAL and its precursor, CCMF on ALDH, GST and cell viability in liver, the target tissue for its metabolism and toxicity. A known toxin, HNE, which is also a substrate for ALDH and GST, was used for comparison. Interspecies difference in metabolism of FBM is well documented, therefore, human tissue was deemed most relevant and used for these studies. ATPAL inhibited ALDH and GST activities and led to a loss of hepatocyte viability. Several fold greater concentrations of CCMF were necessary to demonstrate a similar degree of ALDH inhibition or cytotoxicity as observed with ATPAL. This is consistent with CCMF requiring prior conversion to the more proximate toxin, ATPAL. GSH was shown to protect against ALDH inhibition by ATPAL. In this context, ALDH and GST are detoxifying pathways and their inhibition would lead to an accumulation of reactive species from FBM metabolism and/or metabolism of other endogenous or exogenous compounds and predisposing to or causing toxicity. Therefore, mechanisms of reactive aldehydes toxicity could include direct interaction with critical cellular macromolecules or indirect interference with cellular detoxification mechanisms.
authors.affiliation: Laboratory of Clinical Pharmacology, CDER, US FDA, MOD-1, Laurel, MD 20708, USA. kapetani@mail.nih.gov
authors.forename: Izet M
authors.initials: IM
authors.lastname: Kapetanovic
authors.forename: Cynthia D
authors.initials: CD
authors.lastname: Torchin
authors.forename: John M
authors.initials: JM
authors.lastname: Strong
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Yonekawa
authors.forename: Chuang
authors.initials: C
authors.lastname: Lu
authors.forename: Albert P
authors.initials: AP
authors.lastname: Li
authors.forename: Christine M
authors.initials: CM
authors.lastname: Dieckhaus
authors.forename: Webster L
authors.initials: WL
authors.lastname: Santos
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Macdonald
authors.forename: R Duane
authors.initials: RD
authors.lastname: Sofia
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Kupferberg
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D000927:Anticonvulsants / Q000378:metabolism / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000078328:Felbamate; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D048448:Phenylcarbamates; D011409:Propylene Glycols / Q000378:metabolism / Q000633:toxicity*
chemical_list: D000447:Aldehydes; D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D048448:Phenylcarbamates; D011409:Propylene Glycols; C462359:tert-4-hydroxy-2-nonenal; D000444:Aldehyde Dehydrogenase; D005982:Glutathione Transferase; D000078328:Felbamate