title: Blood acylpeptide hydrolase activity is a sensitive marker for exposure to some organophosphate toxicants.
abstract: Acylpeptide hydrolase (APH) unblocks N-acetyl peptides. It is a major serine hydrolase in rat blood, brain, and liver detected by derivatization with (3)H-diisopropyl fluorophosphate (DFP) or a biotinylated fluorophosphonate. Although APH does not appear to be a primary target of acute poisoning by organophosphorus (OP) compounds, the inhibitor specificity of this secondary target is largely unknown. This study fills the gap and emphasizes blood APH as a potential marker of OP exposure. The most potent in vitro inhibitors for human erythrocyte and mouse brain APH are DFP (IC(50) 11-17 nM), chlorpyrifos oxon (IC(50) 21-71 nM), dichlorvos (IC(50) 230-560 nM), naled (IC(50) 370-870 nM), and their analogs with modified alkyl substituents. (3)H-diisopropyl fluorophosphate is a potent inhibitor of mouse blood and brain APH in vivo (ED(50) 0.09-0.2 mg/kg and 0.02-0.03 mg/l for ip and vapor exposure, respectively). Mouse blood and brain APH and blood butyrylcholinesterase (BChE) are of similar sensitivity to DFP in vitro and in vivo (ip and vapor exposure), but APH inhibition is much more persistent in vivo (still >80% inhibition after 4 days). The inhibitory potency of OP pesticides in vivo in mice varies from APH selective (dichlorvos, naled, and trichlorfon), to APH and BChE selective (profenofos and tribufos), to ChE selective or nonselective (many commercial insecticides). Sarin administered ip at a lethal dose to guinea pigs inhibits blood acetylcholinesterase and BChE completely but erythrocyte APH only partially. Blood APH activity is therefore a sensitive marker for exposure to some but not all OP pesticides and chemical warfare agents.
authors.affiliation: Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, California 94720-3112, USA.
authors.forename: Gary B
authors.initials: GB
authors.lastname: Quistad
authors.forename: Rebecka
authors.initials: R
authors.lastname: Klintenberg
authors.forename: John E
authors.initials: JE
authors.lastname: Casida
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D001921:Brain / Q000201:enzymology; D002091:Butyrylcholinesterase / Q000378:metabolism; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D004912:Erythrocytes / Q000201:enzymology; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D051379:Mice; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010447:Peptide Hydrolases / Q000097:blood* / Q000378:metabolism; D010575:Pesticides / Q000633:toxicity*; D010959:Tissue Plasminogen Activator / Q000097:blood / Q000378:metabolism
chemical_list: D015415:Biomarkers; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D009943:Organophosphorus Compounds; D010575:Pesticides; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D010447:Peptide Hydrolases; D018819:Dipeptidyl Peptidase 4; C038220:acylaminoacyl-peptidase; D010959:Tissue Plasminogen Activator