Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.1.7 (acetylcholinesterase)
 28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phenobarbital and some other enzyme-inducers are known to reduce organophosphate toxicity. One suggested mechanism is the induction of liver cytochrome P450 enzymes catalyzing monooxygenation reactions. The aim of the present study was to elucidate the cytochrome P450 subfamily, or P450 isoenzyme(s), participating in the detoxification of diisopropyl fluorophosphate (DFP) in the rat. DFP resulted in a type I spectrum in liver microsomes from phenobarbital- or RP 52028-treated rats (binding constants 0.32 and 0.17 microM, respectively) and in a purified P450 preparation enriched with CYP2B. The spectrum was reversible by metyrapone, an inhibitor of the CYP2B enzyme subfamily. The 7-pentoxyresorufin O-dealkylase activity was inhibited by DFP in liver microsomes from phenobarbital- or RP 52028-treated rats and in a reconstituted system containing the purified CYP2B preparation. In microsomes from phenobarbital-pretreated rats, the inhibition was of a mixed type, i.e., competitive-non-competitive (Km = 0.5 microM; Ki = 6 microM). The microsomal fractions of livers from phenobarbital- or RP 52028-treated rats detoxified DFP effectively in vitro, as measured by a decrease in the DFP inhibition of cholinesterase activity. This detoxification was antagonized by metyrapone and by an antibody raised against purified CYP2B preparation. Clotrimazole, an inhibitor of P450 enzymes, inhibited the detoxification of DFP in rat liver in vivo. A genetically-modified hamster cell line expressing CYP2B1 oxidized NADPH in the presence of DFP. No such oxidation was detected in the parent cell line. These studies suggest that CYP2B1 metabolizes DFP and may significantly contribute to the detoxification of this organophosphate in vivo.
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PMID:P450 enzyme CYP2B catalyzes the detoxification of diisopropyl fluorophosphate. 782 Aug 84

1. The effects of two model inducers of the cytochrome P450 system, phenobarbital (PB) and beta-naphthoflavone (NF), on the toxicity of paraoxon were studied in rats. 2. Paraoxon toxicity was measured by inhibition of brain acetylcholinesterase (AChE) activity. 3. PB treatment did not affect the toxicity of paraoxon, whereas NF increased the inhibition of brain AChE. PB administration slightly increased the activities of some peripheral cholinesterases and carboxylesterases, as well as liver microsomal paraoxonase (Pxase). 4. NF administration, in contrast, decreased the activities of peripheral esterases. Serum Pxase activity was reduced by both inducers. 5. Hepatic CYP2B and CYP1A were markedly induced by PB and NF, respectively. 6. Cytochrome P450 isoenzymes induced by PB or NF seemed not to be critical in the detoxification of paraoxon in vivo. NF caused a general reduction of peripheral esterases, which led to an increase in paraoxon toxicity. 7. The results indicated the great importance of peripheral cholinesterases and carboxylesterases as a detoxifying mechanism of paraoxon. The role of serum paraoxonase was not critical.
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PMID:Effect of phenobarbital and beta-naphthoflavone on activities of different rat esterases after paraoxon exposure. 968 78

Exposure to organophosphate (OP) pesticides can occur in free-living mammals in treated areas. Risk to nontarget animals from OPs usually is assessed with acute exposure data, but exposure of wild animals is likely to be intermittent and chronic. We compared the effects of single or repeated (hourly and daily) exposure to dimethoate on acetylcholinesterase (AChE) activity in laboratory mice to assess the suitability of standard laboratory tests for assessing risk. Mice were exposed either to a single dose (10 or 30 mg/kg) or to short-term repeated (three hourly doses of 10 mg/kg) intraperitoneal doses of dimethoate, and brain and serum AChE activity were measured. No significant difference was found in the degree of inhibition of AChE activity following acute and short-term repeated exposure. In a second experiment, mice were given three daily doses of 10 or 20 mg/kg of dimethoate, and both AChE activity and hepatic cytochrome P450 enzyme activity were measured. Daily exposure resulted in a dose-dependent decline in brain and serum AChE activity, and inhibition increased progressively with successively repeated exposures. However, this effect was relatively small compared to the effect of dose. Cytochrome P450 enzyme activity (CYP2B) was inhibited in the dimethoate-dosed mice. Our results indicate that acute dose-response toxicity studies are suitable models for predicting the likely occurrence of adverse effects from either short- or longer-term exposure of wild mammals to anticholinesterase compounds. Likely differences in exposure pattern between the laboratory and the natural environment are unlikely to bias the predictive power of these studies significantly.
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PMID:A comparison of the effects of single and repeated exposure to an organophosphate insecticide on acetylcholinesterase activity in mammals. 1683 48

Chlorpyrifos is a commonly used insecticide that can be metabolically activated by CYP2B to the acetylcholinesterase inhibitor chlorpyrifos-oxon causing cholinergic overstimulation and neurotoxicity. Rat brain extracts can also activate chlorpyrifos in vitro, and the lack of circulating oxon in serum suggests that metabolic activation within the brain may be responsible for chlorpyrifos neurotoxicity. Rats received intracerebroventricular (ICV) injections of CYP2B mechanism-based inhibitors (MBI), once or repeatedly, followed by chlorpyrifos (62.5-250 mg/kg sc). Rats were assessed for neurochemical (acetylcholinesterase activity), physiological (temperature), and behavioral measures (e.g., gait, righting reflex, arousal, incline angles) at 4 hours 3 days after chlorpyrifos treatment. ICV CYP2B MBIs increased brain chlorpyrifos levels, decreased brain chlorpyrifos-oxon levels, and attenuated the reduction in brain acetylcholinesterase; there was no effect on serum chlorpyrifos levels or acetylcholinesterase activity reduction. Inhibition of brain chlorpyrifos metabolism by CYP2B MBIs blocked centrally mediated hypothermia but not peripherally mediated hyperthermia. A single ICV MBI treatment significantly attenuated chlorpyrifos neurotoxicity mediated behavioral outcomes at 1 day after chlorpyrifos treatment with a gradual worsening of behavioral scores through day 3, suggesting a recovery of brain CYP2B activity and an increase in local chlorpyrifos activation. Daily ICV MBI injections attenuated neurotoxicity across all test days consistent with prolonged inhibition of brain chlorpyrifos activation. Thus, rat brain CYP2B contributes significantly to chlorpyrifos's neurotoxic effects. Variable human brain CYP2B levels, influenced by genetics and environmental exposures, may contribute to interindividual differences in neurotoxicity. Therapeutic inhibition of brain CYP2B could also be explored as a treatment for exposure to CYP2B-activated neurotoxins.
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PMID:Rat brain CYP2B-enzymatic activation of chlorpyrifos to the oxon mediates cholinergic neurotoxicity. 2228 24