Pharmacokinetic Factors in the Neurotoxicities of p-Bromophenylacetylurea and m-Dinitrobenzene.

Xu, Jinsheng (1998). Pharmacokinetic Factors in the Neurotoxicities of p-Bromophenylacetylurea and m-Dinitrobenzene. PhD thesis The Open University.



Conventional approaches to the study of neurotoxicants focus exclusively on the direct action of neurotoxicants on the nervous system. In fact, pharmacokinetic and metabolic factors can greatly modify the effect of neurotoxicants. This thesis presents the investigations of the pharmacokinetic and metabolic factors in chemical-induced neurotoxicities, p-Bromophenylacetylurea (BPAU) and m-dinitrobenzene (m-DNB) were selected as model neurotoxicants. Wistar (LACP) and F344 rats, and the analytical techniques of HPLC, MS and NMR were used in the present studies.

This study has demonstrated that metabolism and pharmacokinetic behaviour of BPAU and m-DNB significantly modified their neurotoxicity. Three metabolites of BPAU, 3-hydroxy-5-(4-bromophenyl)-1,3 -diazapentane-2,4-dione (M1), 4-4-bromo-phenyl)-3-oxapyrrolidine-2,5-dione (M2) and 3-methyl-5-(4-bromophenyl)-1,3-diaza- pentane-2,4-dione (M3), were identified and characterised in this study. Phenylmethanesulfonyl fluoride (PMSF) which can intensify BPAU-induced neuropathy signiflcandy delayed BPAU elimination, increased M1 levels in tissues and decreased M2 concentration in serum This metabolic interaction and neurotoxic synergy between the two compounds represent a distinct model in the mechanistic studies of the promotion of delayed neuropathy. The present study also showed that 1-year old rats which are more susceptible to BPAU-induced neuropathy produced more M1 and less M2 than 6-week old rats.

In vivo and in vitro studies in this thesis also demonstrated that m-DNB can be metabolised in brain. The major metabolite was 3-nitroaniline (3-NA). An activated intermediate, 3-nitrosonitrobenzene (3-NNB) was detected in the cultured astrocytes and endothelial cells. This suggests that metabolic activation may play an important role in m-DNB-induced neurotoxicity. The infusion-lesion model revealed that once a concentration threshold for m-DNB is exceeded, the time which m-DNB is maintained above that threshold is a more important factor in producing brain lesions than a higher transient concentration.

This study has demonstrated that pharmacokinetic approaches have a great potential in understanding chemical-induced neurotoxicity.

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