Certain
esterase inhibitors, such as
carbamates, phosphinates and sulfonyl halides, do not cause neuropathy as some
organophosphates, but they may exacerbate chemical or traumatic insults to axons. This phenomenon is called promotion of axonopathies. Given the biochemical and toxicological characteristics of these compounds, the hypothesis was made that the target of promotion is a
phenyl valerate (PV)
esterase similar to
neuropathy target esterase (NTE), the target of
organophosphate induced delayed
polyneuropathy. However, attempts to identify a PV
esterase in hen peripheral nerve have been, so far, unsuccessful. We tested several
esters, other than PV, as substrates of
esterases from crude homogenate of the hen peripheral nerve. The ideal substrate should be poorly hydrolysed by NTE but extensively by
enzyme(s) that are insensitive to non-promoters, such as
mipafox, and sensitive to promoters, such as phenyl methane
sulfonyl fluoride (PMSF). When phenyl
benzoate (PB) was used as substrate, about 65% of total activity was resistant to the non-promoter
mipafox (up to 0.5 mM, 20 min, pH 8.0), that inhibits NTE and other
esterases. More than 90% of this resistant activity was sensitive to the classical promoter PMSF (1 mM, 20 min, pH 8.0) with an IC(50) of about 0.08 mM (20 min, pH 8.0). On the contrary, the non-promoter p-
toluene sulfonyl fluoride caused only about 10% inhibition at 0.5 mM. Several
esterase inhibitors including,
paraoxon, phenyl benzyl
carbamate, di-n-butyl dichlorovinyl
phosphate and di-isopropyl
fluorophosphate, were tested both in vitro and in vivo for inhibition of this PB activity.
Mipafox-resistant PMSF-sensitive PB
esterase activity(ies) was inhibited by promoters but not by non promoters and neuropathic compounds.