2012
Volume 12, Number 3, pp. 89–97
Endogenous human plasma catalytic bioscavengers for organophosphorus compounds do not protect against the toxicity of chemicals implicated in aerotoxic syndrome: an in vitro study
Patrick Masson,1, 2, 3 Lawrence M. Schopfer,2 Ashima Saxena,4 John Mikler5 and Oksana Lockridge2
1 Laboratoire de Biophysique Moléculaire, Institut de Biologie Structurale, 41 rue Jules Horowitz, 38027 Grenoble, France
2 Eppley Institute and Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
3 Département de Toxicologie, Institut de Recherche Biomédicale des Armées (IRBA)–Centre de Recherches du Service de Santé des Armées (CRSSA), 24 av. des Maquis du Grésivaudan, 38702 La Tronche, France
4 Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD 20910-7500, USA
5 Defence Research & Development Canada (DRDC) – Suffield, Box 4000, Medicine Hat, Alberta, Canada T1A 8K6
Exposure of airline passengers and crew members to fumes from jet engines causes the aerotoxic syndrome. The toxicant is suspected to be cresyl saligenin phosphate (CBDP), the metabolite of tri-o-cresyl phosphate (TOCP), a component of tricresyl phosphate (TCP), the antiwear additive in jet engine lubricants. Another toxic organophosphate (OP) potentially present in jet engine fumes is trimethylolpropane phosphate (TMPP).In vivo detoxification of CBDP and TMPP is a potential source of variability in susceptibility to aerotoxic syndrome. Therefore, to determine whether the human plasma catalytic bioscavengers, paraoxonase (PON-1) and prolidase (PROL), may protect against the toxicity of CBDP and TMPP, we studied the binding and reactivity of these OPs with human PON-1 and PROL. Results showed that these enzymes do not hydrolyse CBDP and TMPP. PROL is not even inhibited by these OPs. PON-1 is competitively inhibited by both OPs with inhibition constants of the order of 10–4 M for CBDP and 10–3 M for TMPP. Such affinities are several orders of magnitude higher than the concentrations encountered in poisoning by CBDP and TMPP. Furthermore, TMPP does not react with the stoichiometric OP bioscavenger, human plasma butyrylcholinesterase (BChE). Therefore, BChE does not protect against TMPP, though it does protect against CBDP. In summary, the human plasma catalytic bioscavengers, paraoxonase and prolidase, do not provide a natural defence against CBDP and TMPP.
Keywords: aerotoxic syndrome, bioscavengers, cresyl saligenin phosphate (CBDP), human paraoxonase, human prolidase, organophosphate poisoning, trimethylolpropane phosphate (TMPP)