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At least 19 recordsLinked to original sources
PubMed1992

Cimetidine-carbaryl interaction in humans: evidence for an active metabolite of carbaryl.

The influence of cimetidine on the pharmacokinetic and pharmacodynamic response to the insecticide carbaryl has been investigated in isolated human erythrocytes (red blood cells; RBC) and after oral administration of 1 mg/kg carbaryl to four normal subjects in the absence or presence of cimetidine (300 mg, 8/hr for 3 days). Carbaryl induced a concentration-dependent reduction of isolated RBC acetylcholinesterase activity requiring 1 microgram/ml to achieve 20% inhibition. Cimetidine also induced a dose-dependent inhibition of RBC acetylcholinesterase activity, but at 40-fold higher concentrations. At high concentrations, cimetidine was additive to carbaryl-induced inhibition of RBC acetylcholinesterase, but exhibited no effect at the therapeutically relevant concentrations (10 micrograms/ml). After oral carbaryl administration to normal subjects, plasma concentrations rapidly rose to a peak, then declined with a half-life of 0.79 +/- 0.47 hr. Oral carbaryl clearance was 5.4 +/- 2.0 l/min. Peak plasma carbaryl concentrations were associated with 27% inhibition of RBC acetylcholinesterase activity, and the concentration associated with a reduction of RBC acetylcholinesterase activity of 20% was 0.02 microgram/ml. The terminal half-life for the dynamic response was 2.6 +/- 1.5 hr. After pretreatment with cimetidine, peak plasma carbaryl concentrations doubled and clearance was reduced (to 2.5 +/- 1.5 l/min) (P less than .05). However, half-life remained unchanged. Despite increased carbaryl levels, the maximum inhibition of RBC acetylcholinesterase activity was significantly reduced, and the concentration of carbaryl required to achieve 20% inhibition of RBC acetylcholinesterase activity was increased to approximately 0.5 microgram/ml. These results are consistent with the hypothesis that carbaryl is metabolized by drug-metabolizing enzymes that can be inhibited by cimetidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholinesterase↗
PubMed2006

Activation of the aryl hydrocarbon receptor by carbaryl: Computational evidence of the ability of carbaryl to assume a planar conformation.

It has been accepted that aryl hydrocarbon receptor (AhR) ligands are compounds with two or more aromatic rings in a coplanar conformation. Although general agreement exists that carbaryl is able to activate the AhR, it has been proposed that such activation could occur through alternative pathways without ligand binding. This idea was supported by studies showing a planar conformation of carbaryl as unlikely. The objective of the present work was to clarify the process of AhR activation by carbaryl. In rat H4IIE cells permanently transfected with a luciferase gene under the indirect control of AhR, incubation with carbaryl led to an increase of luminescence. Ligand binding to the AhR was studied by means of a cell-free in vitro system in which the activation of AhR can occur only by ligand binding. In this system, exposure to carbaryl also led to activation of AhR. These results were similar to those obtained with the AhR model ligand beta-naphthoflavone, although this compound exhibited higher potency than carbaryl in both assays. By means of computational modeling (molecular mechanics and quantum chemical calculations), the structural characteristics and electrostatic properties of carbaryl were described in detail, and it was observed that the substituent at C-1 and the naphthyl ring were not coplanar. Assuming that carbaryl would interact with the AhR through a hydrogen bond, this interaction was studied computationally using hydrogen fluoride as a model H-bond donor. Under this situation, the stabilization energy of the carbaryl molecule would permit it to adopt a planar conformation. These results are in accordance with the mechanism traditionally accepted for AhR activation: Binding of ligands in a planar conformation.

Animals↗
PubMed2006

Inhibition of mitochondrial bioenergetics by carbaryl is only evident for higher concentrations -- Relevance for carbaryl toxicity mechanisms.

Although pesticides have been useful in agriculture pest control, there is a considerable risk for human health and damage to ecosystems. Carbaryl is a carbamate often taken as a safe insecticide, although data on metabolic activities is still scarce, viz. mitochondrial toxicity. Therefore, it is the goal of this work to assay the compound on isolated mitochondria, a biochemical model already used with other pesticides. Mitochondria isolated from the livers of Wistar rats were assayed for bioenergetic parameters, namely mitochondrial respiration, membrane potential, membrane integrity and enzyme activities. For higher concentrations, it was observed that carbaryl has a depressive effect on mitochondrial respiration and on the generation of mitochondrial membrane potential, but with preservation of membrane integrity. A locus between Complex II and III appears particularly affected and the mitochondrial phosphorylation system relatively insensitive. Therefore, carbaryl inhibits mitochondrial respiration without affecting the phosphorylation complex. Carbaryl is toxic for mitochondria, although at concentrations higher as compared with other insecticide compounds. Mitochondrial toxicity should be excluded as one of the primary causes for carbaryl immediate toxicity, as concluded from the range of concentrations where carbaryl shows effective mitochondrial toxicity.

Animals↗
PubMed1991

Hydrolysis of carbaryl by a Pseudomonas sp. and construction of a microbial consortium that completely metabolizes carbaryl.

Two Pseudomonas spp. (isolates 50552 and 50581) isolated from soil degraded 1-naphthol and carbaryl, an N-methylcarbamate pesticide, respectively. They utilized these compounds as a sole source of carbon. 1-Naphthol was completely metabolized to CO2 by the isolate 50552, while the carbaryl was first hydrolyzed to 1-naphthol and then converted into a brown-colored compound by the isolate 50581. The colored metabolite was not degraded, but 1-naphthol produced by the isolate 50581 during the exponential phase of growth was metabolized by the isolate 50552. The two isolates were used to construct a bacterial consortium which completely catabolized carbaryl to CO2. No metabolite was detected in the cell cultures of the consortium. The isolate 50581 harbored a 50-kb plasmid pCD1, while no plasmid was detected in the isolate 50552. The isolated bacteria individually or as a consortium may be used for detoxification of certain industrial and agricultural wastes.

Biodegradation, Environmental↗
PubMed2002

In vitro metabolism of carbaryl by human cytochrome P450 and its inhibition by chlorpyrifos.

Carbaryl is a widely used anticholinesterase carbamate insecticide. Although previous studies have demonstrated that carbaryl can be metabolized by cytochrome P450 (CYP), the identification and characterization of CYP isoforms involved in metabolism have not been described either in humans or in experimental animals. The in vitro metabolic activities of human liver microsomes (HLM) and human cytochrome P450 (CYP) isoforms toward carbaryl were investigated in this study. The three major metabolites, i.e. 5-hydroxycarbaryl, 4-hydroxycarbaryl and carbaryl methylol, were identified after incubation of carbaryl with HLM or individual CYP isoforms and analysis by HPLC. Most of the 16 human CYP isoforms studied showed some metabolic activity toward carbaryl. CYP1A1 and 1A2 had the greatest ability to form 5-hydroxycarbaryl, while CYP3A4 and CYP1A1 were the most active in generation of 4-hydroxycarbaryl. The production of carbaryl methylol was primarily the result of metabolism by CYP2B6. Differential activities toward carbaryl were observed among five selected individual HLM samples with the largest difference occurring in the production of carbaryl methylol. Co-incubations of carbaryl and chlorpyrifos in HLM greatly inhibited carbaryl metabolism. The ability of HLM to metabolize carbaryl was also reduced by pre-incubation of HLM with chlorpyrifos. Chlorpyrifos inhibited the generation of carbaryl methylol, catalyzed predominately by CYP2B6, more than other pathways, correlating with an earlier observation that chlorpyrifos is metabolized to its oxon primarily by CYP2B6. Therefore, carbaryl metabolism in humans and its interaction with other chemicals is reflected by the concentration of CYP isoforms in HLM and their activities in the metabolic pathways for carbaryl. (Supported by NCDA Environmental Trust Fund)

Adult↗
PubMed1986

Pentylenetetrazol: effect on carbaryl-induced changes of serotonin metabolism in pons-medulla of rat brain.

Oral administration of carbaryl to adult male albino rats produced a dose dependent increase in the steady state level of 5-hydroxytryptamine (5-HT) at 1.00 h in pons-medulla (PM). 5-Hydroxyindole acetic acid (5-HIAA) concentration was significantly elevated only in response to a higher dose of this pesticide under similar conditions. A time course study with carbaryl and pentylenetetrazol (PTZ) showed a characteristic elevation of the steady state level of 5-HT in PM, but the 5-HIAA level was significantly elevated at 0.5 h only after carbaryl treatment. No significant change of the 5-HIAA level was evident after administration of PTZ alone or in combination with carbaryl. Tryptophan concentration was significantly elevated in PM at 0.5 h after carbaryl treatment and at 1.0 h after carbaryl + PTZ treatment. No significant change of tryptophan concentration was evident after the administration of PTZ alone under similar conditions. Measurement of (1) pargyline induced (a) accumulation of 5-HT and (b) depletion of 5-HIAA levels, and (2) probenecid-induced accumulation of 5-HIAA level in presence and absence of carbaryl and revealed that carbaryl accelerated the synthesis as well as the breakdown of 5-HT, whereas PTZ alone or in combination with carbaryl accelerated the synthesis of 5-HT without affecting its catabolism. The potency of this pesticide in elevating the pargyline-induced accumulation of 5-HT is in the order of carbaryl + PTZ greater than PTZ congruent to carbaryl. These results suggest that the carbaryl-induced increase in the synthesis of 5-HT is potentiated, and the turnover is reduced, in PM when PTZ is administered to the carbaryl-intoxicated rats.

Animals↗
PubMed2006

Carbaryl inhibits basal and FSH-induced progesterone biosynthesis of primary human granulosa-lutein cells.

Carbaryl is known to impede female reproductive function, however, the mechanisms through which the adverse effects are mediated are not clearly elucidated. In order to get insight into the mechanisms, this study was conducted to raise fresh concerns about the potential effects of carbaryl on steroidogenesis by primary human granulosa-lutein cells (hGLCs) and explore the possible nature of this action. hGLCs were co-incubated with various concentrations of carbaryl at 0, 1, 5, 25, 125 micromol/L for 24 h to examine effects of this carbamate pesticide on progesterone accumulation. We observed that the carbaryl inhibited basal and FSH-induced progesterone production in a dose-dependent manner. We also investigated the effects of carbaryl on 22(R)-hydroxycholesterol (22R-HC)-stimulated progesterone yield, basal and FSH-stimulated StAR gene expression and cyclic adenosine monophosphate (cAMP) production, as well as forskolin (non-specific activator of adenylyl cyclase)-induced progesterone and cAMP production of hGLCs. We found that the decreased progesterone biosynthesis was accompanied with a reduced cAMP abundance on both basal and FSH-induced condition. Furthermore, our results demonstrated that the 22R-HC could remove the carbaryl-induced restraint of progesterone biosynthesis, suggesting that carbaryl caused a disruption of cholesterol transport across mitochondrial membranes, which was further confirmed by the observation that carbaryl inhibited the gene expression of steroidogenic acute regulatory protein (StAR). In addition, the inhibitory effects of carbaryl on progesterone and cAMP production were completely reversed by addition of forskolin to the cell culture, which indicated a repaired site on the upstream components of adenylate cyclase or adenylate cyclase per se by carbaryl in the cAMP-mediated signal pathway. All the effects mentioned above were not due to a detrimental action of carbaryl on cell viability by MTS assay. In conclusion, carbaryl may inhibit steroidogenesis, at least in part, by obstructing the delivery of cholesterol over mitochondrial membranes and attenuating cAMP generation.

Carbaryl↗
PubMed1989

Effect of carbaryl on the respiration, glycolysis and gluconeogenesis in isolated liver cells.

The effects of 1-naphthyl-N-methylcarbamate (carbaryl) upon respiration, glycolysis and gluconeogenesis in isolated rat hepatocytes was studied. The carbaryl at 0.01; 0.1 and 1.0 mM were dissolved in 1% dimethylsulphoxide. Concentrations of carbaryl at 1.0 mM reduces oxygen consumption. The decrease in the metabolic production of CO2 is significant at even the lowest of the concentrations. The utilization of glucose and the endogenous production of lactic is unaffected by treatment with carbaryl. The net glycolytic flux is decreased. On the other hand, the carbaryl inhibits lactate-gluconeogenesis at all concentrations of substrate studied. Gluconeogenesis from fructose or pyruvate or alanine is also inhibited by carbaryl 1 mM. Carbaryl decreases the lactic dehydrogenase activity but this diminution is only significant for the greatest concentration assayed. The activity of glucose-6-phosphatase is enhanced by carbaryl, but the increase is only significant for 1 mM carbaryl. The glutamic-oxalacetic transferase cytoplasmic and mitochondrial activities are inhibited by 0.1 mM and 1.0 mM carbaryl. Carbaryl decreases glucose production by hepatic cells, and suggests that the carbaryl-induced hyperglycemia in the fasted animal would be due to deficiencies in the peripheral utilization of the glucose.

Animals↗
PubMed1980

Excretion and disposition of [14C]carbaryl in pregnant, non-pregnant and foetal tissues of the rat after acute administration.

1. Non-pregnant or pregnant Sprague-Dawley rats on the 18th and 19th days of gestation were injected i.p. with a tracter dose (2.8 microCi/kg) of either [ring-14C]carbaryl or [carbonyl-14C]carbaryl. Distribution of total 14C was examined in foetal, maternal and non-pregnant rat tissues. Pregnancy alters the disposition and excretion of carbaryl. 2. Carbaryl crossed the placenta and was rapidly distributed in all foetal tissues. Highest concentrations were seen in foetal kidney. At 8 h after injection, foetal brain, heart and lung all contained more 14C, on a weight basis, than their maternal organ counterparts. Elimination from the whole foetus was biphasic, and after 8 h approx. 3% of the dose was still present in the whole foetus. 3. Significantly more 14CO2 was exhaled by the pregnant rat during 8 h than by non-pregnant. Urinary excretion of 14C after dosage with [ring-14C]carbaryl was significantly less in pregnant than in non-pregnant rats. 4. Kinetically, the tissue distribution of 14C from carbaryl or metabolites was biphasic in pregnant and non-pregnant animals. [14C]carbaryl concn. declined rapidly for 1 to 2 h. After 2 h the 14C levels from animals dosed with [ring-14C]carbaryl declined more slowly. 5. The pattern of 14C distribution was more complicated after injection of [carbonyl-14C]carbaryl. The 14C activity increased in the animal tissues after 2 h, in contrast to animals dosed with [ring-14C]carbaryl. Non-pregnant animals treated with [carbonyl-14C]carbaryl did not show a similar pattern of distribution. Carbamylated tissue proteins may, after time, release some bound carbonyl-14C label, causing the increase in 14C activity seen between 2 and 8 h. However, this does not necessarily imply uptake of the intact carbamate.

Animals↗
PubMed1983

Evaluation of cellular and humoral mechanisms of carbaryl-induced reticuloendothelial phagocytic depression.

The simultaneous injection of carbaryl and colloidal carbon phagocytized by the reticuloendothelial cells results in competition between the two substances in favor of the carbon particles. Experiments with opsonized carbaryl suggest that the decrease in carbaryl blood clearance by the colloid is mediated by a depletion of serum opsonins. Following blockade, the liver carbaryl uptake was depressed in the control group (17%), while it was increased in the opsonized group (12%). With all preparations of carbaryl, opsonized or non-opsonized, colloidal carbon produced a slight and variable increase in carbaryl uptake by the spleen and lungs. These results indicate that, besides the uptake of carbaryl by the hepatocytes, other clearance sites must also be considered such as the Kupffer cells and other liver sinusoidal cells. Moreover our results show that intravenous administration of carbaryl induces a state of phagocytic depression as indicated by impaired intravascular phagocytosis and depressed hepatic uptake of the reticuloendothelial (RE)-test colloidal suspension. The results obtained from injection of opsonized colloidal particles during carbaryl-induced RE-depression, and the fact that carbaryl and carbon are both opsonized by the same serum factor, suggest that the mechanisms of RE-blockade involve selective hepatic and splenic macrophage failure and depletion of serum opsonins. According to our enzymatic investigation, this failure of the RE system to incorporate colloids during carbaryl--RE-blockade could be due to a defect in the activity of macrophage membrane-bound serine esterase.

Animals↗
PubMed2005

[Effects of carbaryl production exposure on the sperm and semen quality of occupational male workers].

OBJECTIVE: To analyse the male reproductive toxicity of carbaryl. METHODS: Thirty-one male carbaryl exposure workers and 46 male administrators in the office in a pesticide factory were selected as the exposure group and internal control group respectively, and 22 male administrators in a center for disease control and prevention were served as the external control group. In order to evaluate the exposure levels, the concentrations of carbaryl, methyl isocyanate, ammonia and phenol in the ambient air of the work place in these three groups were monitored simultaneously for three consecutive days. Moreover, three workers in the exposure group and the external control group were selected to evaluate the amount of carbaryl of individual and dermal contamination for three consecutive days. After the semen were collected according to the standard method, the workers'semen qualities were analysed with WHO method, the sperm morphology and the sperm motility were evaluated using micro-cell slide spectrum technology and computer assisted sperm analysis (CASA) respectively. RESULTS: In the exposure group, the concentrations of carbaryl and phenol (52.41 mg/m(3) and 0.08 mg/m(3) respectively) were significantly higher than those in the internal and external control group (P < 0.01 or P < 0.05). Furthermore, in the carbaryl exposure area the geometric mean concentration of carbaryl with the individual sampling was 7.38 mg/m(3), and the geometric mean of dermal contamination detected in the carbaryl exposure area was 862.47 mg/m(2). Carbaryl was not found in the external control area (P < 0.01). The seminal volume [(2.39 +/- 1.44) ml] and the sperm motility [(1.77 +/- 0.61) grade] were significantly lower than those in the external control group (P < 0.05), and sperm motion parameters such as linearity (LIN, 39.89% +/- 6.00%), straightness (STR, 71.51% +/- 11.22%), straight line velocity [VSL, (26.29 +/- 7.84) microm/s] and beat cross frequency [BCF, (3.99 +/- 1.55) Hz] were lower than those in the internal and external control group (P < 0.05), while the abnormal rates of viscidity, sperm motility and total aberration rate were higher than those in the external control group (P < 0.05). CONCLUSION: Occupational exposure to carbaryl production can affect the workers'sperm and semen quality to certain extent.

Adult↗
PubMed1982

Exposure of urban applicators to carbaryl.

Thirty-eight urban volunteers from the Lincoln and Omaha, Nebraska areas were monitored for carbaryl exposure during the summer of 1979. All volunteers were involved in the application of carbaryl incidental to their employment or leisure activities. The investigators made no attempt to affect the method of carbaryl application. The mean rates of carbaryl exposure were 3.85 and 0.26 microgram cm-2 hr-1, respectively, for the outside of the clothing and the skin beneath the clothing; clothing apparently provided an effective barrier to carbaryl penetration. The rate of carbaryl exposure to the hands of applicators was 2.36 and 24.96 micrograms cm-21 hr-1, respectively, for applicators with and without gloves. The maximum dermal exposure recorded in this study was 2.86 mg kg-1 hr-1 which is significantly less than the stimated dermal LD50 value for carbaryl (4000 mg kg-1). The maximum air concentration of carbaryl was 0.28 microgram L-1. Only a small mean decrease was found in the applicators serum (-1.01%) or erythrocyte (-1.39%) acetylcholinesterase activity. Although some applicators had decreases in either serum or erythrocyte acetylcholinesterase activity greater than 20%, an equal number had increases of the same magnitude. The mean total carbaryl exposure to the applicators, expressed as a percent of toxic dose per hr, was 0.01%, with a maximum estimated exposure of 0.08%.

Acetylcholinesterase↗
PubMed1976

Identification by physical means of organic moieties of conjugates produced from carbaryl by tobacco cells in suspension culture.

Carbaryl (1-naphthyl methylcarbamate), labeled with 14C in the C1-naphthyl, carbonyl, or N-methyl position, was introduced into the culture medium of tobacco cells in suspension culture. Following incubation, cells were homogenized in water, centrifugated, and supernatants hydrolyzed with beta-glucosidase or HCl. Organic moieties (moieties) were characterized by two-dimensional thin-layer chromatography (TLC), and many were subsequently identified by infrared and mass spectrometry. On the basis of the data obtained with 14C1-naphthyl-labeled carbaryl, it appeared that 18.4% of the total characterized metabolites represented unconjugated N-CH2OH- carbaryl [1-naphthyl N-(hydroxymethyl)carbamate], excreted by the cells into the culture medium. The metabolites found in the cells primarily consisted of conjugates of 1-naphthol (73.6% of the total characterized metabolites) and N-CH2OH-carbaryl (2.5%). Conjugates of 7-hydroxycarbaryl (7-hydroxy-1-napthyl methylcarbamate), 4-hydroxycarbaryl (4-hydroxy-1-naphthyl methylcarbamate), and 5-hydroxycarbaryl (5-hydroxy-1-naphthyl methylcarbamate) were also detected in small amounts. Of five unknown 14C1-naphthyl-labeled carbaryl metabolites, three were tentatively characterized as: O-1-naphthylcholesterol (Cholest-5-en-3beta-yl-1-napthol: 3.0%); an unconjugated hydroxylated 1,4-dihydro-1,4-epiperoxynapththalene (1.4%); and an acidlabile, beta-glucosidase-resistant conjugate of a cis-dihydrodiol of 1-naphthol (0.3%; other than the trans-5,6-dihydrodiol). The cholesterol derivative may represent a new "detoxification mechanism" in plants; the epiperoxide may help to elucidate plant oxidation mechanisms. A new TLC procedure was developed which successfully separated the acetate derivative of N-hydroxycarbaryl (1-naphthyl N-hydroxy-N-methylcarbamate) from 12 other common moieties of carbaryl metabolites and their acetate derivatives. A new two-dimensional TLC system was developed for the separation of underivatized N-hydroxycarbaryl from 14 other moieties of carbaryl metabolites; two additional two-dimensional TLC systems were utilized for moiety separations. With these TLC procedures, no conjugated or unconjugated N-hydroxycarbaryl could be detected in any tobacco cell culture fraction after incubation of cells in medium containing radiolabeled carbaryl. Authentic 14C1-naphthyl-labeled N-CH2OH-carbaryl was shown to be converted to desmethylcarbaryl (1-naphthylcarbamate) 97%) and 1-naphthol (3%) by 0.1N HCl hydrolysis.

Carbaryl↗