Inhibition and recovery of maternal and fetal cholinesterase enzyme activity following a single cutaneous dose of methyl parathion and diazinon, alone and in combination, in pregnant rats.
Pregnant Sprague-Dawley rats (14-18 days of gestation) were treated with a single cutaneous subclinical dose(s) of 10 mg kg(-1) (15% of LD(50)) of methyl parathion (O,O-dimethyl O-4-nitrophenyl phosphorothioate) and 65 mg kg(-1) (15% of LD(50)) of diazinon (O,O)-diethyl O-2-isopropyl-6-methylpyrimidinyl phosphorothioate, and their combination. Animals were sacrificed at 1, 2, 4, 12, 24, 48, 72, and 96 h after dosing. Inhibition of maternal and fetal cholinesterase enzyme activity has been determined. Methyl parathion significantly inhibited maternal and fetal brain acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BuChE) activity within 24 h after dosing. Diazinon and a mixture of methyl parathion and diazinon caused lesser inhibition compared with methyl parathion alone. Recovery of maternal and fetal brain AChE activity was in the order of diazinon > combination of diazinon and methyl parathion > methyl parathion 96 h after dosing. Although fetal plasma BuChE activity recovered to 100% of control within 96 h of application, maternal BuChE activity remained inhibited to 55% and 32% of control 96 h after application of methyl parathion and a mixture of methyl parathion and diazinon, respectively. Following a single dermal dose of methyl parathion, the activity of maternal liver BuChE was 63% of control 2 h after dosing, whereas inhibition of placental AChE or BuChE activity occurred 12 and 1 h following a single dose of methyl parathion, corresponding to activities of 63% and 54% of control, respectively. Diazinon, alone or in combination with methyl parathion, did not inhibit significantly the maternal liver BuChE or placental AChE and BuChE activity. The results suggest that dermal application of a single dose of methyl parathion and diazinon, alone or in combination, has an easy access into maternal and fetal tissues, resulting in inhibition of cholinesterase enzymes. The lower inhibitory effect of the combination of methyl parathion and diazinon might be due to competition of diazinon with methyl parathion for cytochrome P-450 enzymes, resulting in formation of the potent cholinesterase inhibitor methyl paraoxon. The faster recovery of fetal cholinesterase enzymes is attributed to the rapid de novo synthesis of cholinesterase fetal tissues compared with the mother.
Abu-Qare
A W
AW
Department of Pharmacology and Cancer Biology, PO Box 3813, Duke University Medical Center, Durham, NC 27710, USA.
Abou-Donia
M B
MB
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology; D002091:Butyrylcholinesterase / Q000097:blood*; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics*; D003976:Diazinon / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007279:Injections, Subcutaneous; D008099:Liver / Q000201:enzymology; D008431:Maternal-Fetal Exchange; D008743:Methyl Parathion / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D011270:Pregnancy, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013997:Time Factors
D002800:Cholinesterase Inhibitors; D008743:Methyl Parathion; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D003976:Diazinon