The effect of hepatic mixed-function oxidase enzyme inducers on the development of tri-o-tolyl phosphate-induced delayed neurotoxicity.
Adult White Leghorn hens were divided into 15 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 beta-naphthoflavone (beta NF) 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 beta NF 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 beta NF may be due to induction of enzymes responsible for the inactivation of the neurotoxic metabolite.
D000818:Animals; D001259:Ataxia / Q000139:chemically induced; D001571:Benzoflavones / Q000494:pharmacology; D001711:Biotransformation; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors; D002645:Chickens; D003408:Cresols / Q000633:toxicity*; D004790:Enzyme Induction; D005260:Female; D008099:Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D009420:Nervous System / Q000187:drug effects*; D010634:Phenobarbital / Q000494:pharmacology; D014317:Tritolyl Phosphates / Q000378:metabolism / Q000633:toxicity*; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D003408:Cresols; D014317:Tritolyl Phosphates; D019324:beta-Naphthoflavone; D006899:Mixed Function Oxygenases; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; C025541:tri-o-cresyl phosphate; D010634:Phenobarbital