Neurotoxic potentiation is related to a metabolic interaction between p-bromophenylacetylurea and phenylmethanesulfonyl fluoride.
This study investigated the neurotoxic potentiation and metabolic interaction between p-bromophenylacetylurea (BPAU) and phenylmethanesulfonyl fluoride (PMSF). The results showed that F344 rats given two successive daily doses of 150 mg/kg BPAU developed a moderate degree of ataxia. When rats were coadministrated a single intraperitoneal dose of 100 mg/kg PMSF either 1 day before, or 4 h or 1 day after the two daily doses of BPAU, the severity of ataxia was significantly increased. No such effect was observed when PMSF was given 4 days after BPAU, although this time point was still prior to the development of the neuropathy. The enhancement or potentiation of neuropathy by PMSF was thus seen only at times when parent BPAU was present in the target tissues. A pharmacokinetic study showed that PMSF increased the concentrations of BPAU and its metabolite, N'-hydroxy-p-bromophenylacetylurea (M1), in tissues and decreased the concentration of the metabolite 4-(4-bromophenyl)-3-oxapyrrolidine-2,5-dione (M2) in serum. This indicated that PMSF inhibited the M2 pathway and more BPAU was metabolized via the M1 pathway. This increased both BPAU and M1 levels in tissues and hence would have increased BPAU-induced neurotoxicity. We conclude that PMSF does not need to act directly on target sites to potentiate BPAU-induced neurotoxicity, since its interference with BPAU metabolism was sufficient to account for the increase in BPAU neurotoxicity. Thus a metabolic interaction underlies the neurotoxic potentiation between these two compounds rather than the target site interaction seen between PMSF and neuropathic organophosphates. This study is the first to demonstrate that interference with the metabolism of BPAU is an important aspect of the potentiation of BPAU-induced neurotoxicity.
Xu
J
J
Faculty of Applied Sciences, University of the West of England, Bristol, United Kingdom.
Lister
T
T
Purcell
W M
WM
Ray
D E
DE
D000818:Animals; D001259:Ataxia / Q000139:chemically induced; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004357:Drug Synergism; D005260:Female; D010664:Phenylmethylsulfonyl Fluoride / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution; D014508:Urea / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity
C004506:4-bromophenylacetylurea; D010664:Phenylmethylsulfonyl Fluoride; D014508:Urea