Role of uptake of [14C]valine into protein in the development of tolerance to diisopropylphosphorofluoridate (DFP) toxicity.
In a subchronic toxicity study male Sprague-Dawley rats were daily treated with diisopropylphosphorofluoridate (DFP) (0.5 mg/kg, sc) for 14 days. Maximum signs of anticholinesterase toxicity were observed during Days 4 and 5 comparable to those seen 10-15 min following a single sublethal dosage (1.5 mg DFP/kg, sc). Signs disappeared after Days 6-7 of exposure and rats became apparently normal during the remainder of the treatment period. Significant hypothermia was seen following the second to fifth doses with maximum effect after the fifth injection. Subsequent injections of DFP did not cause any reduction in temperature. Incorporation of [14C]valine was measured 24 hr after the 5th and 14th injections of DFP, at a time when body temperature had recovered to control values. The rate of in vivo incorporation of [14C]valine was measured 0.5, 1.0, and 2.0 hr after a subcutaneous injection of L-[1-14C]valine at a dose of 5 microCi/mmol/100 g body wt. After five injections the rate of L-[1-14C]valine uptake into the free amino acid pool and the incorporation into the protein bound pool was significantly (p less than 0.01) reduced in discrete brain regions, liver, kidney, and skeletal muscles. At the end of the 14-day treatment, protein synthesis in all the skeletal muscles tested had recovered completely (p greater than 0.01) to the values of nontreated control animals. In brain, liver, and kidney, however, no recovery was seen during this period. The recovery of protein synthesis in skeletal muscle may be one of the mechanisms that lead to tolerance development during prolonged administration of subacute concentrations of DFP.
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002250:Carbon Radioisotopes; D004361:Drug Tolerance; D007035:Hypothermia / Q000139:chemically induced; D007279:Injections, Subcutaneous; D007531:Isoflurophate / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D014176:Protein Biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D014633:Valine / Q000378:metabolism*
D002250:Carbon Radioisotopes; D007531:Isoflurophate; D000110:Acetylcholinesterase; D014633:Valine