Inhibition of cholinesterases by DRP and induction of organophosphate-detoxicating enzymes in rats.
1. The inhibition of cholinesterase and carboxylesterase activities in the diisopropyl fluorophosphate (DFP) intoxication, and the inducibility of organophosphate (OP) detoxicating enzymes was studied in rats. 2. In phenobarbital (PB)-, but not in beta-naphthoflavone (NF)-pretreated rats, the activities of DFP-inhibited cholinesterases were 70-120% higher than in non-pretreated rats. Also the inhibition of the microsomal and cytosolic carboxylesterase activity in liver was efficiently antagonized by BP, but not by NF. 3. In vitro the microsomes from PB-treated rats detoxicated DFP probably by O-dealkylation, since no fluoride was released from DFP. Glutathione S-transferase did not detoxicate DFP. 4. 7-Pentoxyresorufin O-dealkylase, a specific enzyme of cytochrome P450IIB subfamily, was induced by PB, flumecinol, isosafrole and NF by 167- 61-, 26- and 1.6-fold, respectively. 7-Ethoxyresorufin O-deethylase, a marker enzyme of cytochrome P450IA subfamily, was induced by those agents 5-, 4-, 31- and 94-fold, given in the same order. Glutathione S-transferase, paraoxonase and DFPase activities were increased 0-72% by the tested inducers. 5. The results suggest that the cytochrome P450IIB subfamily, inducible by PB, participates in DFP detoxication by O-dealkylation. Its induction probably causes the protection against the cholinesterase inhibition by OPs.
Kaliste-Korhonen
E
E
Department of Physiology, University of Kuopio, Finland.
Törrönen
R
R
Ylitalo
P
P
Hänninen
O
O
D000110:Acetylcholinesterase / Q000096:biosynthesis; D000818:Animals; D043303:Aryldialkylphosphatase; D001571:Benzoflavones / Q000494:pharmacology; D002265:Carboxylic Ester Hydrolases / Q000096:biosynthesis; D002800:Cholinesterase Inhibitors; D002802:Cholinesterases / Q000096:biosynthesis; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D004950:Esterases; D005982:Glutathione Transferase / Q000096:biosynthesis; D006867:Hydrolases / Q000096:biosynthesis; D008658:Inactivation, Metabolic; D007531:Isoflurophate / Q000378:metabolism / Q000633:toxicity*; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis; D044345:Phosphoric Triester Hydrolases; D051381:Rats; D011919:Rats, Inbred Strains; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D002800:Cholinesterase Inhibitors; D007531:Isoflurophate; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase; D006867:Hydrolases; D004950:Esterases; D002265:Carboxylic Ester Hydrolases; C019734:arylesterase; D000110:Acetylcholinesterase; D002802:Cholinesterases; D010744:Phosphoric Monoester Hydrolases; D044345:Phosphoric Triester Hydrolases; D043303:Aryldialkylphosphatase; C020061:diisopropyl-fluorophosphatase; D010634:Phenobarbital