Inhibition of cholinesterase enzymes following a single dermal dose of chlorpyrifos and methyl parathion, alone and in combination, in pregnant rats.
Pregnant Sprague-Dawley rats (14-18 d of gestation) were treated with either a single dermal subclinical dose of 30 mg/kg (15% of dermal LD50) chlorpyrifos (O,O-diethyl-O-[3,5,6-trichloro-2-pyridinyl] phosphorothioate) or a single dermal subclinical dose of 10 mg/kg (15% of dermal LD50) methyl parathion (O,O-dimethyl O-4-nitrophenyl phosphorothioate) or the two in combination. Chlorpyrifos inhibited maternal and fetal brain acetylcholinesterase (AChE) activity within 24 h of dosing, (48% and 67% of control activity, respectively). Following application of methyl parathion, peak inhibition of maternal and fetal brain AChE activity occurred at 48 h and 24 h after dosing (17% and 48% of control activity, respectively). A combination of chlorpyrifos and methyl parathion produced peak inhibition of maternal and fetal brain AChE activity at 24 h postdosing (35% and 73% of control activity, respectively). Maternal and fetal brain AChE activity recovered to various degrees of percentage of control 96 h after dosing. Application of methyl parathion or chlorpyrifos alone or in combination significantly inhibited maternal plasma butyrylcholinesterase (BuChE) activity. No significant inhibition of fetal plasma BuChE activity was detected. Peak inhibition of maternal liver BuChE occurred 24 h after application of methyl parathion or chlorpyrifos alone or in combination (64%, 80%, and 61% of control activity, respectively). Significant inhibition of placental AChE occurred within 24 h after application of methyl parathion or chlorpyrifos alone or in combination. The results suggest that methyl parathion and chlorpyrifos, alone or in combination, were rapidly distributed in maternal and fetal tissues, resulting in rapid inhibition of cholinesterase enzyme activities. The lower inhibitory effect of the combination could be due to competition between chlorpyrifos and methyl parathion for cytochrome P-450 enzymes, resulting in inhibition of the formation of the potent cholinesterase inhibitor oxon forms. The faster recovery of fetal plasma BuChE is attributed to the de novo synthesis of cholinesterase by fetal tissues compared to maternal tissues.
Abu-Qare
A W
AW
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Abdel-Rahman
A
A
Brownie
C
C
Kishk
A M
AM
Abou-Donia
M B
MB
D000110:Acetylcholinesterase / Q000187:drug effects / Q000378:metabolism; D000279:Administration, Cutaneous; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000187:drug effects / Q000378:metabolism; D004390:Chlorpyrifos / Q000493:pharmacokinetics / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D007306:Insecticides / Q000493:pharmacokinetics / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D018811:Maternal Exposure / Q000009:adverse effects*; D008743:Methyl Parathion / Q000493:pharmacokinetics / Q000633:toxicity*; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D002800:Cholinesterase Inhibitors; D007306:Insecticides; D008743:Methyl Parathion; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D004390:Chlorpyrifos