Pharmacokinetic Analysis of Increased Toxicity of 2-sec-Butylphenyl Methylcarbamate (BPMC) by Fenitrothion Pretreatment in Mice

Pharmacokinetk Analysis of Increased Toxicity of 2-sec-ButylphenylMethylcarbamate (BPMC) by Fenitrothion Pretreatment in Mice.TSUDA, S., MIYAOKA, T., IWASAKI, M., AND SHIRASU, Y. (1984).Fundam. Appl. Toxicol. 4, 724–730. The potentiating effectof O,O-dimethyl O-(3-methyl-4-nitrophenyl) phosphorothioate(fenitrothion) on the toxicity of 2-sec-butylphenyl methylcarbamate(BPMC) in male mice was analyzed pharmacokinetically. The animalspretreated by dietary administration of 1000 ppm fenitrothionfor 1 week (4.4% of the po LD50 daily) did not show toxic symptomsexcept for a slight decrease in body weight In the fenitrothion-pretreatedmice, toxicity of fenitrothion was not changed but a fivefoldpotentiation was observed in po and ip acute lethality and athreefold potentiation of iv lethality of BPMC. Toxic signsafter BPMC administration were similar regardless of fenitrothionpretreatment or of route of administration. Fenitrothion pretreatmentfollowed by BPMC administration (20 mg/kg po or 8 mg/kg iv,approximate LD5 in the pretreated mice) significantly increasedthe plasma BPMC concentration and the total area under the plasmaconcentration versus time curve (AUG_0-. The pretreatment increasedthe oral AUC_0-, more greatly than the iv AUC_0-, (for po, 6.3-fold;for iv, 2.0-fold). The oral systemic availability of BPMC (fractionreaching systemic circulation) was increased by fenitrothiontreatment to 3.3-fold. These results suggest that a major causeof the potentiation may be the increase in amount of BPMC inthe systemic circulation.     

Potentiation of Acute Toxicity of 2-sec-Butylphenyl N-Methylcarbamate (BPMC) by Fenthion in Mice

Potentiation of Acute Toxicity of 2-sec-Butylphenyl N-methylcarbamate(BPMC) by Fenthion in Mice. MIYAOKA, T., TAKAHASHI, H., TSUDA,S., AND SHIRASU, Y. (1984). Fundam. Appl. Toxicol. 4, 802–807.This study was undertaken to determine whether interactionsof toxicologic importance might occur during combined exposureof male mice to 2-sec-butylphenyl N-methylcarbamate (BPMC) andO,O-dimethyl O-(3-methyl-4-methylthiophenyl)phosphorothioate(fenthion). The equitoxic (administration of BPMC and fenthionresulted in only a 1.6-fold potentiation compared to the expectedLD50. However, 1 hr oral pretreatment with 3 (1/100 LD50), 7.5,15, and 30 mg/kg of fenthion resulted in 5-, 9-, 12-, and 15-foldpotentiation of the acute oral toxicity of BPMC, respectively.This fenthion pretreatment caused significant increases in theBPMC plasma concentrations and in the area under the concentration-timecurve. The increase of the plasma concentrations of BPMC dependedupon the fenthion dose and was associated with that of the potencyratio. The pretreatment of fenthion prolonged the hexobarbitalsleeping time. The plasma concentrations of BPMC after the administrationof a dose of LD2.5 (20 mg/kg) in fenthion-pretreated mice wereclearly lower than those of a dose of LD2.5 (195 mg/kg) in nontreatedmice. These results suggested that fenthion pretreatment causedthe potentiation of the acute toxicity of BPMC partially bythe inhibition of detoxification of BPMC.     

Contribution of Monoaminergic Nervous System in Potentiation of 2-sec-Butylphenyl N-Methylcarbamate (BPMC) Toxicity by Malathion in Male Mice

Contribution of Monoaminergic Nervous System in Potentiationof 2-sec-Butylphenyl N-Methylcarbamate (BPMC) Toxicity by Malathionin Male Mice. TAKAHASHI, H., TANAKA, J., TSUDA, S., and SHIRASU,Y. (1987). Fundam. Appl. Toxicol. 8, 415–422. Malathion-inducedmarked potentiation of BPMC toxicity (about fivefold) was analyzedby measuring LD50 as an index of acute toxicity. The acute lethalityof BPMC was decreased by muscarinic blockers (atropine, methylatropine,or trihexyphenidyl) or a monoamine oxidase inhibitor (pargyline)and increased by a monoamine depleter (reserpine) or a dopaminergicblocker (haloperidol). The potentiation observed with BPMC andmalathion was decreased by the muscarinic blockers, monoaminedepleters (reserpine, -methyl-p-tyrosine), an -noradrenergicblocker (phen-tolamine), or haloperidol. The acute toxicitiesof other N-methylcarbamates MPMC (3,4-di-methylphenyl N-methylcarbamate),MTMC (3-methylphenyl N-methylcarbamate), NAC (1-naphthyl N-methylcarbamate),and XMC (3,5-dimethylphenyl N-methylcarbamate) were potentiatedby malathion to a lesser degree than that of BPMC. Atropineprotected against the lethalities of all N-methylcarbamates.Reserpine or haloperidol potentiated the lethalities of N-methylcarbamateswith a similar tendency toward malathion. When the inhibitoryeffect of each N-methylcarbamate on brain acetylcholinesterase(AChE) was compared with its LD50, among five N-methylcarbamatesBPMC had particularly strong anti-AChE activity. This characteristicof BPMC was not observed after the treatment with reserpine.These results suggest that BPMC may act not only on cholinergicnerves as an anti-AChE, but also on monoaminergic nerves whichantagonize the lethal cholinergic effect. Malathion might inhibitthe effect of BPMC on the monoaminergic nerves, thereby markedlypotentiating the lethal effect of BPMC.     

Metabolism of aspirin and procaine in mice pretreated with O-4-nitrophenyl methyl(phenyl)phosphinate or O-4-nitrophenyl diphenylphosphinate

Concentrations of [carboxyl-14C]procaine in blood of mice were increased threefold for 27 min by exposure to O-4-nitrophenyl diphenylphosphinate 2 hr prior to [carboxyl-14C]procaine injection ip, while there was no effect of O-4-nitrophenyl methyl(phenyl)phosphinate pretreatment. There was no effect of either organophosphinate on the primary hydrolysis of [acetyl-l-14C]aspirin when assessed by the expiration of [14C]carbon dioxide; however, O-4-nitrophenyl diphenylphosphinate pretreatment produced transient increases in blood concentrations of both [carboxyl-14C]aspirin and [carboxyl-14C]salicylic acid following administration of [carboxyl-14C]aspirin. Liver carboxylesterase activity in O-4-nitrophenyl diphenylphosphinate pretreated mice was 11% of control activity. These results indicate the potential for drug interaction with O-4-nitrophenyl diphenylphosphinate but not with O-4-nitrophenyl methyl(phenyl)phosphinate. It appears that liver carboxylesterase activity has a minor role in hydrolysis of aspirin in vivo, but may be more important in procaine metabolism.     

A broad-spectrum organophosphate pesticide O,O-dimethyl O-4-nitrophenyl phosphorothioate (methyl parathion) adversely affects the structure and function of male accessory reproductive organs in the rat

Methyl parathion (MP) is an organophosphate pesticide used in agriculture, but also illegally used to spray homes and businesses to control insects. The present study was designed to investigate adverse effects of MP on accessory reproductive organs. Male Wistar rats aged 13–14 weeks were treated and sacrificed as follows. Experiment 1: 0.0 (water vehicle), 1.75, 3.5 or 7 mg/kg (i.p.) for 5 days and sacrificed on day 14; experiment 2: 0.0, 0.5 or 1 mg/kg (i.p.) for 12 days and sacrificed on day 130; experiment 3: 0.0, 0.5 or 1 mg/kg (i.p.) for 12 days and sacrificed on day 77; experiment 4: 0.0, 0.75 or 1.5 mg/kg (i.p.) for 25 days and sacrificed on day 17 and experiment 5: 0.0 or 3.5 mg/kg (p.o.) for 25 days and sacrificed on day 17, after the last exposure. The accessory reproductive organs were removed, weighed and processed for histopathological analysis. Structural qualitative changes such as epithelial cell morphology and luminal observations were carried out for each organ in all experiments. Epididymis of one side was homogenized and biochemical estimations of acid phosphatase (ACP), cholesterol, total protein, uric acid, and Vitamin C were conducted by calorimetric methods in experiments 4 and 5. In experiment 1 the organ weights did not change; in experiment 2, the epididymal weight increased (P < 0.001); in experiment 3, the weights of ductus deferens decreased at 1 mg/kg and that of seminal vesicle decreased at both dose-levels (P < 0.001). In experiments 4 and 5, weights of epididymis and prostate decreased, whereas in experiment 5, weights of ductus deferens and seminal vesicle increased (P < 0.05–0.001). The sperm density was normal in control, moderately decreased in experiment 1 at 3.5 and 7 mg/kg; in experiment 2 at 1 mg/kg, and in experiment 5 at 3.5 mg/kg, and severely decreased in experiment 3 at 1 mg/kg and in experiment 4 at both dose-levels. The epithelial necrosis and nuclear pyknosis were seen in experiments 1, 3, 4 and 5, whereas nuclear degeneration was seen in experiment 1 and 4 and germ cells in the lumina of epididymis were seen in experiment 4. The nuclear pyknosis in the ductus deferens was seen in all experiments, except at 1.75 mg/kg in experiment 1 and at 0.5 mg/kg in experiment 3. Brush border disruption in the ductus deferens was seen in experiments 1 and 4; sperms were seen in the lumen in experiment 1 at 7 mg/kg, and in experiments 4 and 5. The vacuoles in the epithelium were seen in experiments 1 and 4 and immature germ cells were seen in the lumen in experiment 4. The ACP and Vitamin C levels decreased in experiment 4 at both dose-levels, and in experiment 5 all biochemical parameters tested found decreased (P < 0.01–0.001). The present results indicate that MP affects the structure and function of accessory reproductive organs in the rat.     

Acute and Long Term Effects of 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) in Tests of Nociception in Mice

Abstract: Acute and long term changes in nociception after administration of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) 80 mg/kg (four injections of 20 mg/kg given at two hr intervals) were investigated in mice. MPTP caused shivering, lacrimation, salivation, teeth chattering and fur erection a few minutes after drug injection, but all these behavioural changes were normalized within 30 min., when the first behavioural testing was performed. No significant alteration in general behaviour, sensorimotor performance or body temperature could be detected at the time of nociceptive testing. The acute effects of MPTP on nociception were a reduced response latency in the tail flick test and a prolonged response latency compared to controls in the constant temperature hot plate test. No significant effects of MPTP were found in the increasing temperature hot plate test. The long term effects were a reduced response latency both in the tail flick test and the constant temperature hot plate test, indicating that the MPTP induced lesions of dopaminergic pathways result in hyperalgesia. In the increasing temperature hot plate test and the formalin test, no significant long term changes were demonstrated. Seven days after injection, the dopamine content was reduced to 62% of control values in striatum, to 51% in the rest of the forebrain, and to 41% in the spinal cord. Noradrenaline levels were only slightly and transiently reduced. Serotonin levels were not affected 7 days after injection, but 14 days after injection, a great increase was found in the forebrain and in the spinal cord. The results suggest that dopaminergic systems tonically inhibit nociception. A functional adaptation starts to take place about one week after lesion, making an investigation of the time course important in studies of the functional effects of MPTP induced lesions.     

天然化合物6-羟基-2-甲基-2-(4-甲基-3-戊烯基)-2H-苯并吡喃的合成

６羟基２甲基２（４甲基３戊烯基）２Ｈ苯并吡喃是从ＰｈａｃｅｌｉａｉｘｏｄｅｓＫｅｌｏｇｇ．中分离出的具有抗脂质氧化作用的天然化合物．报道以１，４环己二酮为起始原料经３步合成此天然化合物的过程．     

Darstellung,Kristallstruktur und Wirkung von 2-Methyl-3-(4-oxo-3-phenyl-thiazolidin-2-ylidenamino)-4-(3H)-chinazolinon

Quinazolinones, I: Preparation, Crystal Structure, and Activity of 2-Methyl-3-(4-oxo-3-phenylthiazolidine-2-ylidenamino)-4(3H)-quinazolinone The cyclisation of 1-(3,4-dihydro-2-methyl-4-oxo-3H-quinazoline-3-yl)-3-phenylthiourea (2) with chloroacetic acid leads to 2-methyl-3-(4-oxo-3-phenyl-thiazolidine-2-ylidenamino)-4(3H)-quinazolinone (3) and not to the isomer 4 . The crystal structure of 3 has been determined and refined until R = 0.0715. Compound 3 possesses good hypnotic and anticonvulsant activities.     

Delayed neurotoxicity of O-ethyl O-4-nitrophenyl phenylphosphonothioate: Subchronic (90 days) oral administration in hens

Delayed neurotoxicity in hens was produced following daily oral administration of 0.1, 0.5, 1.0, 2.5, 5.0, and 10.0 mg/kg of technical (85%) O-ethyl O-4-nitrophenyl phenylphosphonothioate (EPN) in gelatin capsules for 90 days. Daily, three groups of hens were given empty gelatin capsules, 10 mg/kg of tri-o-cresyl phosphate (TOCP), or 1 mg/kg of parathion (O,O-diethyl O-4-nitrophenyl phenylphosphorothioate) and served as gelatin capsule controls, positive controls, and negative controls, respectively. TOCP-Treated hens developed delayed neurotoxicity, and those given parathion showed leg weakness with subsequent recovery when the administration of this agent had stopped. The clinical condition of most ataxic hens deteriorated during the 30-day observation period following the end of the oral administration of EPN. Severity of the clinical condition depended on the size of the daily ingested dose, i.e., while hens given small doses showed only ataxia, those treated with large doses progressed to paralysis and died. Days of administration and “total administered dose” before onset of ataxia depended on the daily dose. Degeneration of myelin and axons in the spinal cord was the most consistent histologic change and was identical to that found in TOCP control hens. Only one hen showed sciatic nerve degeneration. Livers from two hens given the highest dose of EPN manifested a moderate degree of hemosiderosis. Plasma cholin esterase was significantly inhibited in all surviving hens given EPN or TOCP at the end of the observation period. A group of hens treated daily with 0.01 mg/kg of EPN showed no abnormality in gait or behavior, and its plasma cholinesterase activity was not significantly different from that of the control. Hens treated with parathion had plasma cholinesterase activity comparable to that of the control 30 days after the administration of the last dose.     

Subchronic Toxicity, Metabolism, and Pharmacokinetics of the Aminobenzamide Anticonvulsant Ameltolide (LY2O1 116) in Rhesus Monkeys

Studies were undertaken to define the subchronic toxicologicprofile of ameltolide, an aminobenzamide anticonvulsant, inyoung adult rhesus monkeys. Daily doses of ameltolide, dissolvedin 10% aqueous acacia, were administered orally via nasogastricintubation at dosages of 5, 10, 20, 45, and 100 mg/kg. Deathsoccurred in two monkeys, one each at 45 and 100 mg/kg, whichwere directly attributable to the effects of the compound. Theexact cause of death in these monkeys was not readily apparent.A third monkey (100 mg/kg) was killed moribund on Day 82 ofthe study due to conditions not directly related to treatment.Clinical signs in monkeys treated with 100 mg/kg included convulsions, diarrhea, weakness, inappetance, vomition, and ataxia.Plasma concentrations of the N-acetyl metabolite of ameltolidewere greater than parent drug concentrations by one to two ordersof magnitude. Mean area under the plasma-time curve (AUC) valuesfor ameltolide were larger than expected at doses of 20 mg/kgor greater, while AUC values for the metabolite were less thanexpected at 45 and 100 mg/kg. These findings suggest a saturationof metabolism and/or excretion at the two higher doses. Similarnonlinearity was seen with mean peak concentrations for bothparent and metabolite. No specific target organ toxicity wasfound on histological evaluation of tissue sections. Methemoglobinconcentration was increased in monkeys given 45 or 100 mg ameltolide/kg.This change was not considered to be toxicologically importantas there were no corroborative clinical, gross, or histopathologicalfindings. A meltolide administered by nasogastric intubationat doses up to 20 mg/kg/day for 3 months did not cause any toxicologicallyimportant alterations in rhesus monkeys.     

Dynamic Epigenetic Changes Involved in Testicular Toxicity Induced by Di‐2‐(Ethylhexyl) Phthalate in Mice

Abstract: The aim of this study was to analyse epigenetic (specifically, DNA methylation) change in testes induced by maternal exposure to di‐2‐(ethylhexyl) phthalate (DEHP) in mice. Testicular dysgenesis syndrome was induced in foetuses by maternal exposure to DEHP. High‐performance liquid chromatography was performed to analyse DNA methylation status, and expression levels of the DNA methyltransferases were examined by quantitative real‐time polymerase chain reaction and western blotting. DEHP significantly had more than 10% relative increase in the global DNA methylation and also increased DNA methyltransferases’ expression. Changes in DNA methylation may play an important role in abnormal testicular function caused by environmental factors such as maternal exposure to DEHP, which may be one possible mechanism of DEHP‐mediated testicular toxicity.     

Toxicity of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD)

In summary, the toxicity of TCDD has been comprehensively examined in multiple acute, subchronic, and chronic studies. Acute toxicity studies have shown marked species differences, with up to a 10,000-fold difference between the single oral LD50 dose for the guinea pig and hamster. TCDD is capable of causing an acnegenic response in man and a similar skin response in certain animals. It is also a potent inducer of microsomal enzymes in some but not all species. A dose-related suppression of cell-mediated immunity has been observed at higher dose levels in laboratory animals but not in humans manifesting TCDD-induced acnegenic response. TCDD causes a dose-related teratogenic response in mice, with the no-adverse-effect level of 0.1 micrograms TCDD/kg/day. In rats, TCDD causes embryo- and fetotoxicity above the no-adverse-effect level of 0.03-0.125 micrograms/kg/day. Dose-related reproductive effects have also been noted in monkeys at doses that elicit maternal toxicity, and additional long-term studies are presently underway. A multigeneration reproduction study as well as a lifetime chronic toxicity study have been completed with TCDD in rats; in both studies, the no-adverse-effect level was found to be 0.001 microgram TCDD/kg/day. Numerous mutagenic studies have been performed using in vitro plant and microbial test systems as well as in vivo tests in mammals and man. A mutagenic response was noted in a few of the vitro test systems, but there are no definitive in vivo correlates of TCDD mutagenicity in higher mammals or man. TCDD has been studied for carcinogenic potential in rats and mice. There is good correlation of the results, with a carcinogenic response noted in both species only after long-term ingestion of higher dose levels that induce toxicity. No carcinogenic response occurred at continuous dose levels of 0.001-0.0014 micrograms/kg/day in rats and 0.001-0.03 micrograms/kg/day in mice. Data presently available are more supportive of a nongenetic (?promotor) rather than a genetic mechanism of carcinogenesis. The most recent research, some of which is still underway, indicates that the biologic uptake and toxicity of TCDD may be significantly decreased if the TCDD is adsorbed onto carbon or soil particles. This information is helpful in hazard assessment of exposure to TCDD.     

Nucleophile Substitution im Verlauf der Baker-Venkataraman-Umlagerung, 4. Mitt.: Reaktivität von methoxylierten 1-(2-Hydroxyaryl)-3-(2-nitrophenyl)-propan-1,3-dionen

Nucleophilic Substitution in Course of the Baker-Venkataraman Rearrangement, IV: Reactivity of Methoxylated 1-(2-Hydroxyaryl)-3-(2-nitrophenyl)-propane-1,3-diones The reactivity of the 1,3-diketones 1 and 2 on heating with K₂CO₃ in boiling DMF is investigated and the formation of the 2′-hydroxyflavones 5a and 6a is demonstrated.     

Stereochemie substituierter Glutarsäuren, 1. Mitt. (±)-threo- und erythro-2-Methyl-3-phenylglutarsäuren

Stereochemistry of Substituted Glutaric Acids, I: (±)-threo- and erythro-2-methyl-3-phenylglutaric Acids Syntheses of (±)-threo-and erythro-2-methyl-3-phenylglutaric acids ( 5,6 ) via the (±)-threo- and erythro-2-phenylbutane-1,1,3-tricarboxylic acids ( 3, 4 ) is described. The configurations of the products were determined.     

Contribution of monoaminergic nervous system in potentiation of 2-sec-butylphenylN-methylcarbamate (BPMC) toxicity by malathion in male mice

Malathion-induced marked potentiation of BPMC toxicity (about fivefold) was analyzed by measuring LD50 as an index of acute toxicity. The acute lethality of BPMC was decreased by muscarinic blockers (atropine, methylatropine, or trihexyphenidyl) or a monoamine oxidase inhibitor (pargyline) and increased by a monoamine depleter (reserpine) or a dopaminergic blocker (haloperidol). The potentiation observed with BPMC and malathion was decreased by the muscarinic blockers, monoamine depleters (reserpine, α-methyl-p-tyrosine), an α-noradrenergic blocker (phentolamine), or haloperidol. The acute toxicities of other N-methylcarbamates MPMC (3,4-dimethylphenyl N-methylcarbamate), MTMC (3-methylphenyl N-methylcarbamate), NAC (1-naphthyl N-methylcarbamate), and XMC (3,5-dimethylphenyl N-methylcarbamate) were potentiated by malathion to a lesser degree than that of BPMC. Atropine protected against the lethalities of all N-methylcarbamates. Reserpine or haloperidol potentiated the lethalities of N-methylcarbamates with a similar tendency toward malathion. When the inhibitory effect of each N-methylcarbamate on brain acetylcholinesterase (AChE) was compared with its LD50, among five N-methylcarbamates BPMC had particularly strong anti-AChE activity. This characteristic of BPMC was not observed after the treatment with reserpine. These results suggest that BPMC may act not only on cholinergic nerves as an anti-AChE, but also on monoaminergic nerves which antagonize the lethal cholinergic effect. Malathion might inhibit the effect of BPMC on the monoaminergic nerves, thereby markedly potentiating the lethal effect of BPMC.     

Synthesis of methyl 2, 6-dimethyl-5-(1′, 2′-dioxo-2′-ethoxyethyl)-4-(3′-nitrophenyl)-1,4-dihydropyridine-3-carboxylate

Hantzch’s type reaction of methyl acetopyruvate(2a), methyl 3-aminocrotonate(3) and 3-nitrobenzaldehyde(4) led to dimethyl 3-acetyl-6-methyl-4-(3′-nitrophenyl)-2,5-dicarboxylate(5a) and methyl 2,6-dimethyl-5-(1′, 2′-dioxo-2′-methoxyethyl)-4-(3′-nitrophenyl)-1,4-dihydropyridine-3-carboxylate(6a) in 26.7 and 9.2% yield, respectively. On the other hand, methyl 2,6-dimethyl-4-(3′-nitrophenyl)-1, 4-dihydropyridine 3-carboxylate(9) was acylated by ethyl oxaly chloride to give methyl 2,6-dimethyl-5-(1′,2′-dioxo-2′-ethoxyethyl)-4-(3′-nitrophenyl)-1,4-dihydropyridine-3-carboxylate(6b) in 76.8% yield.