EFFECTS OF ARSENITE PRETREATMENT ON THE ACUTE TOXICITY OF PARATHION

Parathion (PA) is a phosphorotioate pesticide requiring P-450-mediated oxidations to become activated to paraoxon, or to be metabolised to i ts less toxic metabolites. On the other hand, sodium arsenite [As(III) ] markedly decreases total hepatic P-450 content and dependent monoxyg enase activities. Our aim was to determine the effects of As(III) pret reatment on the acute toxicity of PA and its possible relationship wit h the effects of As(III) on P-450-dependent monooxygenase activities. Adult male Wistar rats were pretreated with As(III) (5.6 mg As(III)/kg , s.c.), and 24 h later given PA (5 to 20 mg/kg, per os). As(III) pret reatment increased the acute toxicity of PA, reducing 38% its median l ethal dose (LD(50)) from 11.68 to 7.21 mg PA/kg. In addition, As(III) pretreatment further decreased the inhibitory effect of PA on brain ac etylcholinesterase activity, reducing 33% the median inhibitory dose ( ID50) from 3.44 to 2.31 mg PA/kg, whereas As(III) alone had no signifi cant effects. As(III) decreased the P-450 content to 87% of control va lues, reduced EROD activity to 74% and BROD activity to 41%; PA produc ed no significant effects on these parameters, whereas the joint admin istration of As(III) + PA produced effects similar to those of As(III) . PROD activity was reduced to 36% of control value by PA, whereas As( III) alone produced no significant effects. However, As(III) pretreatm ent apparently protected against the inhibition of CYP2B1-mediated PRO D activity produced by PA, since PROD values were similar to those of control animals. Our results also indicated that the increase in PA to xicity caused by As(III) pretreatment, could also be related to the CY P2B2 isoform, since decreases in CYP2B2-dependent BROD activity were o bserved in both As(III) and As(III) + PA groups, but not in PA-treated animals, suggesting that CYP2B2 is involved in PA detoxification. Cop yright (C) 1997 Elsevier Science Ireland Ltd.