Variation between three strains of rat: inhibition of neurotoxic esterase and acetylcholinesterase by tri-o-cresyl phosphate.
The present study is concerned with the involvement of strain differences in rodent sensitivity to organophosphorous compound-induced delayed neurotoxicity (OPIDN). The inhibitory effect of three doses of tri-o-cresyl phosphate (TOCP) on neurotoxic esterase (NTE) and acetylcholinesterase (AChE) in brain was compared in three strains of rat: Long-Evans (LE) animals, which have been reported to be sensitive to the neurotoxic effects of TOCP, and Sprague-Dawley (SD) or Fischer 344 (F344) strains, with which negative results have been obtained. Differences in basal levels were found for NTE (LE greater than F344) greater than SD, with a range of 4.87-7.47 nmol phenylvalerate hydrolyzed/mg protein), but not AChE. Strain differences in inhibition by TOCP were found with both assays, with Sprague-Dawley animals being much less sensitive to esterase inhibition than either Long-Evans or Fischer 344 rats. The ED50 values for NTE inhibition were estimated to be 458, 209, and 288 mg/kg for SD, F344, and LE rats, respectively. The ED50 values for AChE inhibition were estimated to be 1007, 408, and 420 mg/kg for SD, F344, and LE rats, respectively. Liver microsomes from the Fischer animals had less cytochrome P-450 than those from the other two strains. Differences in the ability of the strains to either form or inactivate the active metabolite of TOCP may account for the variation observed. While metabolism may play a role in the differences in the level of NTE inhibition in SD rats compared to the LE strain, it cannot account for the lack of sensitivity of the F344 animals to OPIDN. These results may be important in selecting a strain for the study of the toxic effects of organophosphorous compounds in rats.
Carrington
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CD
Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27710.
Abou-Donia
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MB
D000110:Acetylcholinesterase / Q000032:analysis*; D000818:Animals; D001921:Brain / Q000201:enzymology*; D002265:Carboxylic Ester Hydrolases / Q000032:analysis* / Q000037:antagonists & inhibitors; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D003408:Cresols / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000032:analysis*; D008297:Male; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D013045:Species Specificity; D014317:Tritolyl Phosphates / Q000494:pharmacology / Q000633:toxicity*
D002800:Cholinesterase Inhibitors; D003408:Cresols; D014317:Tritolyl Phosphates; D003577:Cytochrome P-450 Enzyme System; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; D000110:Acetylcholinesterase; C025541:tri-o-cresyl phosphate