Paraoxon sensitive phenylvalerate hydrolase in assessing the severity of acute paraoxon poisoning.
BACKGROUND
Intoxications with organophosphorous compounds, especially paraoxon, are frequent. Organophosphorous compounds inhibit serine hydrolases such as acetylcholine, butyrilcholine, and carboxyl esterases although acetylcholine and butyrylcholine are too sensitive to paraoxon to be useful markers of severity. They cannot show a dose-dependent inhibition during an acute organophosphorous compounds exposure because maximal enzyme inhibition is reached at very low organophosphorous compounds concentrations.


OBJECTIVE
To determine in vitro the dose-effect relationship between the activity of the paraoxon-sensitive phenylvalerate hydrolase, a member of the carboxvl esterases family, and the paraoxon dose, and to assess its utility as a putatively less sensitive enzyme marker to monitor the severity of an acute paraoxon intoxication.


METHODS
Phenylvalerate hydrolase and butyrylcholine activities were determined in serum of nine healthy human volunteers before and after addition of different concentrations of paraoxon. The determination of phenyl-valerate hydrolase activity was carried out using a modification of the method described by Johnson. A commercially available kit was used to measure butyrylcholine activity.


RESULTS
Paraoxon inhibits phenyl-valerate hydrolase activity at concentrations above 10 M. Maximal inhibition (approximately 50% of baseline) is achieved at concentrations above 2.5 x 10(-7) M. The IC50 value of paraoxon for phenyl-valerate hydrolase is 34+/-2 nM. The uninhibited phenyl-valerate hydrolase activity is due to paraoxon-resistent isoforms. Paraoxon begins inhibiting butyrylcholine activity at concentrations above 10(-9) M. At concentrations above 5 x 10(-5) M, no butyrylcholine activity is measulrable. The IC50 value of paraoxon for butyrylcholine is 150+/-23 nM.


CONCLUSIONS
The paraoxon-sensitive subunit of phenyl-valerate hydrolase shows dose-dependent inhibition when exposed to paraoxon in vitro, but it is even more sensitive than butyrylcholine to paraoxon inhibition. Determinations of phenyl-valerate hydrolase activity to assess the severity of an acute organophosphorous compounds poisoning cannot be recommended, but phenyl-valerate hydrolase may have utility in worker surveillance.
Petroianu
G
G
Department of Pharmacology and Toxicology, University of Heidelberg at Mannheim, Germany. petroia@rumms.uni-mannheim.de
Kärcher
B
B
Kern
N
N
Bergler
W
W
Rüfer
R
R
D015415:Biomarkers; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000097:blood; D002794:Choline / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007306:Insecticides / Q000506:poisoning*; D008297:Male; D010261:Paraoxon / Q000506:poisoning*
D015415:Biomarkers; D007306:Insecticides; C017100:butyrylcholine; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; D002794:Choline; D010261:Paraoxon