The effect of hepatic mixed‐function oxidase enzyme inducers on the development of tri‐o‐tolyl phosphate‐induced delayed neurotoxicity

Abstract

Adult White Leghorn hens were divided into 75 groups of 10 birds each. Five groups received the prototype mixed‐function oxidase (MFO) enzyme inducer phenobarbital (PB) at a dosage of 50 mg/kg body weight for 3 consecutive days by intraperitoneal (i.p.) injection, 5 groups received the MFO enzyme inducer β‐naphthoflavone (βNF) at 20 mg/kg body weight for 2 consecutive days by i.p. injection, while the remaining 5 groups did not receive an inducer. At 24 h after the last injection, the birds received a single oral dose of tri‐o‐tolyl phosphate (TOTP) (an organophosphate that produces delayed neurotoxicity after metabolic activation by the MFO system) in doses of 62.5, 125, 250, or 500 mg/kg body weight. Corn oil served as the vehicle control. At 48 h after the administration of TOTP, half the birds in each of the 15 groups were killed for determination of whole‐brain neurotoxic esterase (NTE) activity. The remaining birds were observed for the subsequent 19 d for onset of clinical signs characteristic of delayed neurotoxicity. Birds receiving βNF prior to TOTP were protected by the inducer when compared to birds receiving PB + TOTP or TOTP alone. This was indicated by less severe clinical signs as well as less inhibition of whole‐brain NTE activity. The protective effect offered by βNF may be due to induction of enzymes responsible for the inactiva‐tion of the neurotoxic metabolite.