P450 enzyme CYP2B catalyzes the detoxification of diisopropyl fluorophosphate

Laaksonen, Mariitta; Kaliste-Korhonen, Eila; Kärenlampi, Sirpa; Hänninen, Osmo

doi:10.1016/0009-2797(94)03334-5

Cited by 4 publications

(2 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The CYP isoforms CYP1A and CYP2B are involved in the bioactivation of some OPs [22,32‐34]. Exposure of mice to dimethoate did not alter CYP1A1/A2 activity in the present study, which is consistent with findings elsewhere [35]. In the present study, dimethoate caused inhibition of activity.…”

Section: Discussionsupporting

confidence: 92%

A comparison of the effects of single and repeated exposure to an organophosphate insecticide on acetylcholinesterase activity in mammals

Long

Dawson

Shore

2006

Environmental Toxicology and Chemistry

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 92%

A comparison of the effects of single and repeated exposure to an organophosphate insecticide on acetylcholinesterase activity in mammals

Long

Dawson

Shore

2006

Environmental Toxicology and Chemistry

View full text Add to dashboard Cite

show abstract

“…Ketoconazole was reported as an inhibitor previously (13), and the data are comparable. Metyrapone inhibits many P-450-catalyzed reactions (12,22). It is interesting that this compound, also a known inhibitor of carbonyl reductase (18), so potently inhibited, by 83%, AMT formation.…”

Section: Discussionmentioning

confidence: 99%

Zidovudine Azido-Reductase in Human Liver Microsomes: Activation by Ethacrynic Acid, Dipyridamole, and Indomethacin and Inhibition by Human Immunodeficiency Virus Protease Inhibitors

Fayz

Inaba

1998

Antimicrob Agents Chemother

View full text Add to dashboard Cite

AZT (zidovudine, 3-azido-3-deoxythymidine), although metabolized primarily to AZT-glucuronide, is also metabolized to 3-amino-3-deoxythmidine (AMT) by reduction of the azide to an amine. The formation of the myelotoxic metabolite AMT has not been well characterized, but inhibition of AMT formation would be of therapeutic benefit. The aim of this study was to identify compounds that inhibit AMT formation. Using human liver microsomes under anaerobic conditions and [2-14 C]AZT, K m values of AZT azido-reductase, estimated by radio-thin-layer chromatography, were 2.2 to 3.5 mM (n ‫؍‬ 3). Oxygen completely inhibited this NADPHdependent reduction. Thirteen of the 28 compounds tested inhibited the formation of AMT. In addition to the CYP3A4 inhibitors ketoconazole, fluconazole, indinavir, ritonavir, and saquinavir, metyrapone strongly inhibited AMT formation. An unexpected finding was the more-than-twofold increase in AMT formation in the presence of ethacrynic acid, dipyridamole, or indomethacin. Such activation of toxic metabolite formation would impair drug therapy.

show abstract

Function of Plasma and Microsomal Enzymes in Soman Toxicity

Tuovinen

2004

Drug and Chemical Toxicology

View full text Add to dashboard Cite

Such organophosphorous (OP) nerve agents as sarin (isopropyl methylphosphonofluoridate) and soman (pinacolyl methylphosphonofluoridate) are effective inhibitors of acetylcholinesterases (AChE), butyrylcholinesterases (BChE) and carboxylesterases (CaE). The acute toxicity of these compounds in mammals is known to be mediated through inhibition of AChEs, which leads to increased acetylcholine (ACh) levels. The aim of this study was to compare the significance of the plasma CaEs, microsomal CaEs and CYP450 enzymes in detoxification of soman with and without physostigmine treatment. The mice received physostigmine (0.1 mg/kg body wt) intravenously (i.v.) 10 min prior to the intraperitoneal (i.p.) injection of soman (0.400-0.650 mg/kg body wt in olive oil). To avoid possible signs of poisoning, the animals received atropine sulfate (37.5 mg/kg body wt in saline) subcutaneously (s.c.) immediately after the soman administration. In the present study, the inhibitory effect of soman was greater in plasma CaE than in hepatic microsomal CaE fraction. In addition, soman or the combination of soman-physostigmine had no remarkable effect on the microsomal CaE or P4502B activities. In spite of this, however, the microsomal CaEs might offer more protection against multiple LD50s of soman.

show abstract

P450 enzyme CYP2B catalyzes the detoxification of diisopropyl fluorophosphate

Cited by 4 publications

References 31 publications

A comparison of the effects of single and repeated exposure to an organophosphate insecticide on acetylcholinesterase activity in mammals

A comparison of the effects of single and repeated exposure to an organophosphate insecticide on acetylcholinesterase activity in mammals

Zidovudine Azido-Reductase in Human Liver Microsomes: Activation by Ethacrynic Acid, Dipyridamole, and Indomethacin and Inhibition by Human Immunodeficiency Virus Protease Inhibitors

Function of Plasma and Microsomal Enzymes in Soman Toxicity

Contact Info

Product

Resources

About