N., and Bakry, N. M. (2006)

Chem Codes: Chemical of Concern: DZ Rejection Code: BACTERIA.

BIOSIS COPYRIGHT: BIOL ABS. An improved whole-cell technology for detoxifying organophosphate nerve agents was recently developed based on genetically engineered Escherichia coli with organophosphorus hydrolase anchored on the surface. This article reports the immobilization of these novel biocatalysts on nonwoven polypropylene fabric and their applications in detoxifying contaminated wastewaters. The best cell loading (256 mg cell dry weight/g of support or 50 mg cell dry weight/cm2 of support) and subsequent hydrolysis of organophosphate nerve agents were achieved by immobilizing nongrowing cells in a pH 8, 150 mM citrate-phosphate buffer supplemented with 1 mM Co2+ for 48 h via simple adsorption, followed by organophosphate hydrolysis in a pH 8, 50 mM citrate-phosphate buffer supplemented with 0.05 mM Co2+ and 20% methanol at 37ęC. In batch operations, the immobilized cells degraded 100% of 0.8 mM paraoxon, a model organophosphate nerve agent, in approximately 100 min, at a specific rate of 0, Biochemistry/ Biomedical Engineering/ Biophysics/ Engineering/ Metabolism/ Poisoning/ Animals, Laboratory/ Bacteria/Physiology/ Bacteria/Metabolism/ Microbiological Techniques/ Sanitation/ Sewage/ Biodegradation/ Industrial Microbiology/ Enterobacteriaceae

Mulchandani, Priti, Mulchandani, Ashok, Kaneva, Irina, and Chen, Wilfred (1999). Biosensor for direct determination of organophosphate nerve agents. 1. Potentiometric enzyme electrode. Biosensors and Bioelectronics 14: 77-85.
Chem Codes: Chemical of Concern: DZ Rejection Code: METHODS.

A potentiometric enzyme electrode for the direct measurement of organophosphate (OP) nerve agents was developed. The basic element of this enzyme electrode was a pH electrode modified with an immobilized organophosphorus hydrolase (OPH) layer formed by cross-linking OPH with bovine serum albumin (BSA) and glutaraldehyde. OPH catalyses the hydrolysis of organophosphorus pesticides to release protons, the concentration of which is proportional to the amount of hydrolysed substrate. The sensor signal and response time was optimized with respect to the buffer pH, ionic concentration of buffer, temperature, and units of OPH immobilized using paraoxon as substrate. The best sensitivity and response time were obtained using a sensor constructed with 500 IU of OPH and operating in pH 8.5, 1 mM HEPES buffer. Using these conditions, the biosensor was used to measure as low as 2 [mu]M of paraoxon, ethyl parathion, methyl parathion and diazinon. The biosensor was completely stable for at least one month when stored in pH 8.5, 1 mM HEPES +100 mM NaCl buffer at 4[deg]C. Enzyme electrode/ Potentiometric/ Organophosphates/ Nerve agents/ Organophosphorus hydrolase

Mulla, M. S. (1963). Persistence of Mosquito Larvicides in Water. Mosq.News 23: 234-237 .

EcoReference No.: 2677

Chemical of Concern: MLN,MP,DZ; Habitat: A; Effect Codes: MOR; Rejection Code: NO COC(DZ).

Mulla, M. S., Isaak, L. W., and Axelrod, H. (1963). Field Studies on the Effects of Insecticides on Some Aquatic Wildlife Species. J.Econ.Entomol. 56: 184-188.

EcoReference No.: 2090

Chemical of Concern: AZ,DZ,MP,Naled; Habitat: A; Effect Codes: MOR; Rejection Code: NO CONTROL(ALL CHEMS).

Mulla, M. S., Metcalf, R. L., and Isaak, L. W. (1962). Some New and Highly Effective Mosquito Larvicides. Mosq.News 22: 231-238.

EcoReference No.: 14106

Chemical of Concern: DMT,AZ,DZ,MLN,MP,PSM; Habitat: A; Effect Codes: POP; Rejection Code: NO ENDPOINT(ALL CHEMS).

Munn, M. D. and Gilliom, R. J. (2001). Pesticide Toxicity Index for Freshwater Aquatic Organisms. Water-Resour.Investig.Rep.No.01-4077, U.S.Geol.Surv., Sacramento, CA 1-55.

Chem Codes: Chemical of Concern: MCPB,CBL,CPY,DZ,MLN,ACR,ATZ,BFL,BTY,CZE,LNR,MTL,MBZ,PDM,PRO,SZ,TET,TFN Rejection Code: REFS CHECKED/REVIEW.

Murray, A., Rathbone, A. J., and Ray, D. E. (2005). Novel protein targets for organophosphorus pesticides in rat brain. Environmental Toxicology and Pharmacology [Environ. Toxicol. Pharmacol.]. Vol. 19, no. 3, pp. 451-454. May 2005.

Chem Codes: Chemical of Concern: DZ Rejection Code: IN VITRO.

ISSN: 1382-6689

Descriptors: Brain
Descriptors: Acetylcholinesterase
Descriptors: Chlorpyrifos
Descriptors: Malathion
Descriptors: organophosphates
Descriptors: Chlorfenvinphos
Descriptors: proteomics
Descriptors: pirimiphos-methyl
Descriptors: Diazinon
Descriptors: Pesticides (organophosphorus)
Abstract: We report preliminary results from a proteomic search for rat brain protein targets adducted by organophosphorous pesticides. Azamethaphos, chlorfenvinphos, diazinon, malathion and chlorpyrifos oxons (in rat brain homogenates) or pirimiphos-methyl (after systemic treatment) were tested at levels producing no more than 30% inhibition of brain acetylcholinesterase. Loss of reactivity with tritiated diisopropylflurophosphate was taken as proof of adduction by the test organophosphate. In addition to acetylcholinesterase other, previously unrecognised, adducted proteins were detected in total brain protein extracts at 30, 32, 41, 71 and 83 kDa. Azamethiphos adducted all but the 30 and 32 kDa bands, but chlorpyrifos only acetylcholinesterase.
The Ninth Meeting of the International Neurotoxicology Association (INA)
Publisher: Elsevier Science Ltd., The Boulevard Langford Lane Kidlington Oxford OX5 1GB UK, [mailto:[e-mail]], [URL:http://www.elsevier.nl]
DOI: 10.1016/j.etap.2004.12.006
Language: English
English
Publication Type: Journal Article
Classification: X 24134 Pathology
Classification: N3 11104 Mammals (except primates)
Subfile: CSA Neurosciences Abstracts; Toxicology Abstracts

Murray, H. E. and Guthrie, R. K. (1980). Effects of Carbaryl, Diazinon and Malathion on Native Aquatic Populations of Microorganisms. Bull.Environ.Contam.Toxicol. 24: 535-542.

EcoReference No.: 6587

Chemical of Concern: CBL,DZ,MLN; Habitat: A; Effect Codes: PHY,POP; Rejection Code: OK(CBL,MLN),NO ENDPOINT(DZ).

MURRAY, V. SG, WISEMAN HM, DAWLING, S., MORGAN, I., and HOUSE IM (1992). HEALTH EFFECTS OF ORGANOPHOSPHATE SHEEP DIPS. BR MED J; 305 1090.

Chem Codes: Chemical of Concern: DZ Rejection Code: HUMAN HEALTH.

BIOSIS COPYRIGHT: BIOL ABS. RRM LETTER DIAZINON PROPETAMPHOS CHLORFENVINPHOS DIAGNOSIS Biochemistry/ Diagnosis/ Pathology/ Animal/ Toxicology/ Veterinary Medicine/ Animal Diseases/Pathology/ Animal Diseases/Physiopathology/ Artiodactyla

Mustapha, J. and Hill, S. B. (1974). Short-Term Effects of Diazinon on Soil Arthropods. Rev.Ecol.Biol.Sol 11: 197-200.

EcoReference No.: 58114

Chemical of Concern: DZ; Habitat: T; Effect Codes: POP; Rejection Code: NO ENDPOINT(DZ).

Mutch, Elaine and Williams, Faith M. (2003). 565 Do multiple P450 isoforms contribute to diazinon metabolism in man? Toxicology Letters 144: s151.

Chem Codes: Chemical of Concern: DZ Rejection Code: HUMAN HEALTH.

Muzart, Jacques (2003). Palladium-catalysed oxidation of primary and secondary alcohols. Tetrahedron 59: 5789-5816.

Chem Codes: Chemical of Concern: DZ Rejection Code: METHODS.

oxidation/ dehydrogenation/ alcohol/ palladium/ catalysis

Nakagawa, Y., Nakajima, K., Tayama, S., and Moldeus, P. (1995). Metabolism and cytotoxicity of propyl gallate in isolated rat hepatocytes: Effects of a thiol reductant and an esterase inhibitor. Molecular Pharmacology. Vol. 47, no. 5, pp. 1021-1027. 1995.
Chem Codes: Chemical of Concern: DZ Rejection Code: IN VITRO.

ISSN: 0026-395X

Descriptors: hepatocytes
Descriptors: antioxidants
Abstract: The relationship between the metabolism and the cytotoxic effects of propyl gallate (PG) has been studied in freshly isolated rat hepatocytes. Addition of PG (0.5-2.0 mM) to the hepatocytes elicited concentration-dependent cell death, accompanied by decreases in intracellular ATP, adenine nucleotide pools, glutathione, and protein thiols. The rapid loss of ATP preceded the onset of cell death. PG in the hepatocyte suspensions was converted to gallic acid, 4-O-methyl-gallic acid, and other minor products over time. In addition, PG was converted to a dimer [dipropyl-4,4',5,5',6,6'-hexahydroxydiphenate (PG-dimer)] and ellagic acid via autooxidation. In comparisons of the toxic effects of PG and its metabolites at concentrations of 2 mM, the parent compound PG was the most toxic. Pretreatment of hepatocytes with diazinon (100 mu M), an esterase inhibitor, enhanced PG-induced cytotoxicity. This was accompanied by delay of PG loss and inhibition of gallic acid formation. The cytotoxicity of PG was also enhanced by addition of the thiol reductant dithiothreitol (4 mM), although intracellular levels of glutathione and protein thiols were maintained during the incubation period. Dithiothreitol did not affect the hydrolysis of PG to gallic acid by esterases but did delay the conversion of PG and prevented the formation of PG-dimer. In isolated hepatic mitochondria, PG elicited a concentration-dependent increase in the rate of state 4 oxygen consumption, indicating an uncoupling effect. In contrast, PG-dimer inhibited the rate of state 3 oxygen consumption. Based on the respiratory control index, the order of potency for impairment of mitochondria was PG > PG-dimer > gallic acid = 4-O-methyl-gallic acid = ellagic acid = propyl alcohol. These results indicate (a) that PG-induced hepatotoxicity is mediated by the parent compound and not its metabolites, (b) that toxicity is associated with ATP depletion apparently independently of cellular thiol depletion, and (c) that mitochondria may represent critical targets of PG-induced cytotoxicity.
Language: English
English
Publication Type: Journal Article
Classification: X 24153 Metabolism
Subfile: Toxicology Abstracts

Nakagawa, Yoshio and Moldeus, Peter (1998). Mechanism of p-Hydroxybenzoate Ester-induced Mitochondrial Dysfunction and Cytotoxicity in Isolated Rat Hepatocytes. Biochemical Pharmacology 55: 1907-1914.

Chem Codes: Chemical of Concern: DZ Rejection Code: IN VITRO.

The relationship between the metabolism and the cytotoxic effects of the alkyl esters of p-hydroxybenzoic acid (parabens) has been studied in freshly isolated rat hepatocytes. Incubation of hepatocytes with propyl-paraben (0.5 to 2.0 mM) elicited a concentration- and time-dependent cell death that was enhanced when enzymatic hydrolysis of propyl-paraben to p-hydroxybenzoic acid was inhibited by a carboxylesterase inhibitor, diazinon. The cytotoxicity was accompanied by losses of cellular ATP, total adenine nucleotide pools, and reduced glutathione, independently of lipid peroxidation and protein thiol oxidation. In the comparative toxic effects based on cell viability, ATP level, and rhodamine 123 retention, butyl- and isobutyl-parabens were more toxic than propyl- and isopropyl-parabens, and ethyl- and methyl-parabens and p-hydroxybenzoic acid were less toxic than propyl-paraben. The addition of propyl-paraben to isolated hepatic mitochondria reduced state 3 respiration with NAD+-linked substrates (pyruvate plus malate) and/or with an FAD-linked substrate (succinate plus rotenone), whereas state 3 respiration with ascorbate plus tetramethyl-p-phenylenediamine (cytochrome oxidase-linked respiration) was not affected significantly by propyl-paraben. Further, the addition of these parabens caused a concentration-dependent increase in the rate of state 4 oxygen consumption, indicating an uncoupling effect. The rate of state 3 oxygen consumption was inhibited by propyl-paraben, butyl-paraben, and their chain isomers. These results indicate that a) propyl-paraben-induced cytotoxicity is mediated by the parent compound rather than by its metabolite p-hydroxybenzoic acid; b) the toxicity is associated with ATP depletion via impairment of mitochondrial function related to membrane potential and/or oxidative phosphorylation; and c) the toxic potency of parabens to hepatocytes or mitochondria depends on the relative elongation of alkyl side-chains esterified to the carboxyl group of p-hydroxybenzoic acid. p-hydroxybenzoate esters/ parabens/ mitochondrial dysfunction/ cytotoxicity/ rat hepatocytes/ antimicrobial preservative

Nakagawa, Yoshio and Moore, Gregory (1999). Role of mitochondrial membrane permeability transition in p-hydroxybenzoate ester-induced cytotoxicity in rat hepatocytes. Biochemical Pharmacology 58: 811-816.
Chem Codes: Chemical of Concern: DZ Rejection Code: IN VITRO.

The relationship between mitochondrial membrane permeability transition (MPT) and the toxic effects of the alkyl esters of p-hydroxybenzoic acid (parabens) has been studied in mitochondria and hepatocytes isolated from rat liver. MPT has been proposed as a common final pathway in acute cell death through mitochondrial dysfunction. In isolated mitochondria, propyl-paraben (0.1 to 0.5 mM) in the presence of Ca2+ (50 [mu]M) elicited a concentration-dependent induction of mitochondrial swelling dependent on MPT. This was prevented by pretreatment with a specific inhibitor of MPT, cyclosporin A (0.2 [mu]M). For the other parabens tested, the induction of MPT depended on the relative elongation of alkyl side-chains in their molecular structure and was associated with the partition coefficients. In contrast, the induction caused by p-hydroxybenzoic acid was more potent than that of methyl- or ethyl-paraben. The pretreatment of freshly isolated hepatocytes with cyclosporin A (5 [mu]M) and trifluoperazine (10 [mu]M), which inhibit MPT in a synergistic manner, partially but not completely prevented propyl-paraben (1 mM; plus diazinon, 100 [mu]M)-induced cell death, ATP loss, and decreased mitochondrial membrane potential. These results suggest that the onset of paraben-induced cytotoxicity is linked to mitochondrial failure dependent upon induction of MPT accompanied by the mitochondrial depolarization and depletion of cellular ATP through uncoupling of oxidative phosphorylation. p-hydroxybenzoate esters/ parabens/ mitochondrial permeability transition/ mitochondrial dysfunction/ cytotoxicity/ antimicrobial preservative

Nakamura, Mitsunobu, Ouchi, Akihiko, Miki, Masamichi, and Majima, Tetsuro (2001). Photochemical P---O bond fission of aryl diethyl phosphates by a resonant two-photon reaction. Tetrahedron Letters 42: 7447-7449.
Chem Codes: Chemical of Concern: DZ Rejection Code: METHODS.

resonant two-photon reaction/ aryl diethyl phosphate/ P---O bond fission/ KrF excimer laser Photochemical P---OAr bond fission of aryl diethyl phosphates was achieved via a resonant two-photon reaction using a KrF excimer laser, which gave 1,4-dihydroquinone and phenol derivatives.

Nakatsugawa, T., Tolman, N. M., and Dahm, P. A. (1969). Oxidative degradation of diazinon by rat liver microsomes. Biochemical Pharmacology 18: 685-688.
Chem Codes: Chemical of Concern: DZ Rejection Code: METABOLISM.

NANDAN, R. and RAISUDDIN, S. (1992). FUNGAL DEGRADATION OF INDUSTRIAL WASTES AND WASTEWATER. ARORA, D. K., R. P. ELANDER AND K. G. MUKERJI (ED.). HANDBOOK OF APPLIED MYCOLOGY, VOL. 4. FUNGAL BIOTECHNOLOGY. XVII+1114P. MARCEL DEKKER, INC.: NEW YORK, NEW YORK, USA; BASEL, SWITZERLAND. ILLUS. ISBN 0-8247-8501-0.; 0 (0). 1992. 931-961.

Chem Codes: Chemical of Concern: DZ Rejection Code: METABOLISM.

BIOSIS COPYRIGHT: BIOL ABS. RRM POLLUTANTS PESTICIDES TANNERY EFFLUENT PAPER PULP WASTE HEAVY METALS Biochemistry/ Minerals/ Metabolism/ Minerals/Metabolism/ Sanitation/ Sewage/ Air Pollution/ Soil Pollutants/ Water Pollution/ Biodegradation/ Industrial Microbiology/ Biophysics/ Plants/Metabolism/ Herbicides/ Pest Control/ Pesticides/ Fungi

Natarajan, Arvind and Srienc, Friedrich (1999). Dynamics of Glucose Uptake by Single Escherichia coli Cells. Metabolic Engineering 1: 320-333.
Chem Codes: Chemical of Concern: DZ Rejection Code: BACTERIA.

The fluorescent glucose analog, 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG), was used to measure rates of glucose uptake by single Escherichia coli cells. When cell populations were exposed to the glucose analog, 2-NBDG was actively transported and accumulated in single cells to a steady-state level that depended upon its extracellular concentration, the glucose transport capacity of the cells, and the intracellular degradation rate. The dependence upon substrate concentration could be described according to Michaelis-Menten kinetics with apparent saturation constant KM=1.75 [mu]M, and maximum 2-NBDG uptake RATE=197 molecules/cell-second. Specificity of glucose transporters to the analog was confirmed by inhibition of uptake of 2-NBDG by -glucose, 3-o-methyl glucose, and -glucosamine, and lack of inhibition by -glucose. Inhibition of 2-NBDG uptake by -glucose was competitive in nature. The assay for 2-NBDG uptake is extremely sensitive such that the presence of even trace amounts of -glucose in the culture medium (~0.2 [mu]M) is detectable. The rates of single-cell analog uptake were found to increase proportionally with cell size as measured by microscopy or single-cell light scattering intensity. The assay was used to identify and isolate mutant cells with altered glucose uptake characteristics. A mathematical model was developed to provide a theoretical basis for estimating single-cell glucose uptake rates from single-cell 2-NBDG uptake rates. The assay provides a novel means of estimating the instantaneous rates of nutrient depletion in the growth environment during a batch cultivation Escherichia coli/ glucose uptake/ single-cell analysis/ 2-NBDG

NAVARRO GARCIA S, CAMARA MA, BARBA, A., TOLEDANO, R., and LUNA, A. (1992). Incidence of residual levels of organophosphorus insecticides in farm produce in the region of Murcia, Spain: Comparison of intake in the 1985-86 and 1989 campaigns. J APPL TOXICOL; 12 251-254.
Chem Codes: Chemical of Concern: DZ Rejection Code: HUMAN HEALTH.

BIOSIS COPYRIGHT: BIOL ABS. We calculated the effective dietary exposure to 20 organophosphorus insecticides in a sample of residents of the Region of Murcia (Spain). Calculations were based on the contamination of 2310 specimens of citrus fruits, pitted and seedy fruits and vegetables collected in the 1985-86 and 1989 campaigns. A comparison of the results from the two campaigns showed that the mean annual insecticide ingestion determined from the mean consumption of each type of farm produce fell from 7.82 mg to 5.55 mg over the 4-year period studied. The total annual ingestion of insecticides during the 1985-86 and 1989 campaigns was ca. 0.133 and 0.1 mg kg-1 body weight; these values are well below the admissible annual ingestion of insecticides during the 1985-86 and 1989 campaigns was ca. 0.133 and 0.1 mg kg-1 body weight; these values are well below the admissible annual ingestion of 29.565 mg kg-1 body weight. Biochemistry/ Food Technology/ Fruit/ Nuts/ Vegetables/ Food Analysis/ Food Technology/ Food Additives/Poisoning/ Food Additives/Toxicity/ Food Contamination/ Food Poisoning/ Food Preservatives/Poisoning/ Food Preservatives/Toxicity/ Herbicides/ Pest Control/ Pesticides

Nayak, D. N. and Rao, V. R. (1982). Pesticides and Nitrogen Fixation in a Paddy Soil. Soil Biol.Biochem. 14: 207-210.
Chem Codes: Chemical of Concern: BMY,CBF,PRN,DZ,HCCH Rejection Code: BACTERIA.

Nayak, D. N. and Rao, V. Rajaramamohan (1982). Pesticides and nitrogen fixation in a paddy soil. Soil Biology and Biochemistry 14: 207-210.

Chem Codes: Chemical of Concern: DZ Rejection Code: BACTERIA.

The influence of six pesticides, applied singly or in combination, on 15N2 incorporation and C2H2 reduction in a submerged paddy soil was studied under laboratory conditions. While the application of diazinon had no marked effect, benomyl, carbofuran, parathion, nitrofen and [gamma]-HCH, at concentrations close to recommended field application rates (5[mu]g -1) significantly stimulated N2 fixation. Synergistic stimulatory effects of the pesticides on N2 fixation were evident particularly in combinations of carbofuran with benomyl, nitrofen and [gamma]-HCH. On the contrary, diazinon slightly retarded the stimulatory effect of benomyl and carbofuran. Results indicated that the differential effects of pesticides on N2 fixation could be attributed partly to fluctuations in the population of certain groups of N2 fixers in submerged soil.

Nayar, Rajiv, Tilcock, Colin P. S., Hope, Michael J., Cullis, Pieter R., and Schroit, Alan J. (1988). N-Succinyldioleoylphosphatidylethanolamine: structural preferences in pure and mixed model membranes. Biochimica et Biophysica Acta (BBA) - Biomembranes 937: 31-41.
Chem Codes: Chemical of Concern: DZ Rejection Code: METHODS.

The structural preferences of the pH-sensitive phospholipid, N-succinyldioleoylphosphatidylethanolamine (N-succinyl-DOPE), have been examined alone and in mixtures with DOPE by 31P-NMR, fluorescence energy transfer, and freeze-fracture techniques. The basic polymorphic behavior of pure N-succinyl-DOPE and DOPE/N-succinyl-DOPE lipid systems and the influence of calcium and pH were investigated. It is shown that, similar to other negatively charged acidic phospholipids, N-succinyl-DOPE adopts the bilayer organization upon hydration. This structure is maintained at both pH 7.4 and 4.0 in the presence or absence of calcium. In the mixed lipid system, N-succinyl-DOPE can stabilize the non-bilayer lipid, DOPE, into a bilayer structure at both pH 7.4 and 4.0 at more than 10 mol% N-succinyl-DOPE, although a narrow 31P-NMR lineshape is observed at acidic pH values. This corresponds to the presence of smaller vesicles as shown by quasi-elastic light scattering measurements. Addition of equimolar calcium (with respect to N-succinyl-DOPE) to the DOPE/N-succinyl-DOPE systems induces the hexagonal HII phase at both pH values. In unilamellar systems with similar lipid composition the addition of Ca2+ results in membrane fusion as indicated by fluorescence energy-transfer experiments. These findings are discussed with regard to the molecular mechanism of the bilayer to hexagonal HII phase transition and membrane fusion and the utility of N-succinyl-DOPE containing pH-sensitive vesicles as drug-delivery vehicles. Phosphatidylethanolamine/ Hexagonal HII phase/ Liposome/ Freeze-fracture/ Resonance energy transfer/ Model membrane

NCTCOG (1993). Storm Water Discharge Characterization Final Summary Report - Task 2.0. N.Central Texas Counc.of Gov., Dresser and McKee Inc.and Alan Plummer and Assoc.Inc.
Chem Codes: Chemical of Concern: DZ Rejection Code: EFFLUENT.

Ndikum-Moffor, F. M., Schoeb, T. R., and Roberts, S. M. *. (1998). Liver toxicity from norcocaine nitroxide, an N-oxidative metabolite of cocaine. Journal of Pharmacology and Experimental Therapeutics [J. PHARMACOL. EXP. THER.]. Vol. 284, no. 1, pp. 413-419. Jan 1998.

Chem Codes: Chemical of Concern: DZ Rejection Code: METABOLISM.

ISSN: 0022-3565

Descriptors: Indexing in process
Abstract: The oxidative metabolism of cocaine to norcocaine nitroxide has been postulated to be essential for cocaine hepatotoxicity. The hepatic effects of norcocaine nitroxide have never been evaluated in vivo, however. In this study mice were administered norcocaine nitroxide i.p., and hepatotoxicity was assessed using serum alanine aminotransferase activities and microscopic examination of liver tissue. Hepatotoxicity of norcocaine nitroxide was dose-related; significant injury was detectable at doses of 20 to 30 mg/kg i.p., and severe hepatocellular necrosis was observed at doses of 40 and 50 mg/kg. Elevated serum alanine aminotransferase activities peaked between 12 and 18 hr after norcocaine nitroxide treatment. Electron microscopy revealed the presence of pronounced changes in cell morphology as early as 30 min after the norcocaine nitroxide dose. Pretreatment of mice with phenobarbital had no effect on the magnitude of hepatic injury but shifted the intralobular site of necrosis from the midzonal to the periportal region. Pretreatment with diazinon, an esterase inhibitor, increased norcocaine nitroxide-induced liver damage, whereas each of the P450 inhibitors SKF 525A, cimetidine, troleandomycin, ketaconazole and chloramphenicol significantly diminished norcocaine nitroxide hepatotoxicity. The results indicate that norcocaine nitroxide is hepatotoxic and suggest the involvement of P450 enzymes.