Human butyrylcholinesterase as a general prophylactic antidote for nerve agent toxicity. In vitro and in vivo quantitative characterization.
Butyrylcholinesterase purified from human plasma (HuBChE) was evaluated both in vitro and in vivo in mice and rats as a single prophylactic antidote against the lethal effects of highly toxic organophosphates (OP). The variation among the bimolecular rate constants for the inhibition of HuBChE by tabun, VX, sarin, and soman was 10-fold (0.47 to 5.12 x 10(7) M-1 min-1; pH 8.0, 26 degrees). The half-life of HuBChE in blood after its i.v. administration in mice and rats was 21 and 46 hr, respectively. The peak blood-enzyme level was obtained in both species approximately 9-13 hr following i.m. injection of HuBChE, and the fraction of the enzyme activity absorbed into the blood was 0.9 and 0.54 for rats and mice, respectively. The stoichiometry of the in vivo sequestration of the anti-cholinesterase toxicants was consistent with the HuBChE/OP ratio of the molar concentration required to inhibit 100% enzyme activity in vitro. Linear correlation was demonstrated between the blood level of HuBChE and the extent of protection conferred against the toxicity of nerve agents. Pretreatment with HuBChE alone was sufficient not only to increase survivability following exposure to multiple median lethal doses of a wide range of potent OPs, but also to alleviate manifestation of toxic symptoms in mice and rats without the need for additional post-exposure therapy. It appeared that in order to confer protection against lethality nerve agents had to be scavenged to a level below their median lethal dose LD50 within less than one blood circulation time. Since the high rate of sequestration of nerve agents by HuBChE is expected to underlie the activity of the scavenger in other species as well, a reliable extrapolation of its efficacy from experimental animals to humans can be made.
Raveh
L
L
Israel Institute for Biological Research, Ness-Ziona.
Grunwald
J
J
Marcus
D
D
Papier
Y
Y
Cohen
E
E
Ashani
Y
Y
D000818:Animals; D000931:Antidotes; D002091:Butyrylcholinesterase / Q000008:administration & dosage / Q000302:isolation & purification / Q000493:pharmacokinetics*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D006207:Half-Life; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009500:Neutralization Tests; D010755:Organophosphates / Q000633:toxicity*; D009946:Organothiophosphorus Compounds / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012524:Sarin / Q000633:toxicity*; D012999:Soman / Q000633:toxicity*
D000931:Antidotes; D002091:Butyrylcholinesterase; D002800:Cholinesterase Inhibitors; D010755:Organophosphates; D009946:Organothiophosphorus Compounds; D012524:Sarin; D012999:Soman; C009680:VX-agent; C009374:tabun