Inhibitor Report for: Croneton

Ethiofencarb is one of the carbamate compounds, which are, in general, less toxic than organophosphorus insecticides. This is due to their reversible acetylcholinesterase inhibition and relative inability to cross the blood-brain barrier. Generally, ethiofencarb is regarded to be of low toxicity (LD(50) > 200 mg/kg); however, severe poisoning and death are not uncommon. To our knowledge, no measurements of ethiofencarb and its metabolites in human postmortem whole blood have been published. We present here a case report of fatal ethiofencarb intoxication with quantitative analysis of ethiofencarb and its metabolites in ante- and postmortem blood. In addition, postmortem urine was collected and analyzed. A 56-year-old man, who worked as a gardener, was found in poor condition, sitting in his car seat. He had been vomiting. The man was admitted to the local hospital about 1 h later. At admission, he was conscious, but unable to speak clearly. His condition deteriorated, and he developed severe pulmonary edema. Resuscitation with atropine and adrenaline were attempted, but he died approximately 3 h after admission. The analysis of postmortem peripheral blood revealed 0.12 g/100 mL ethanol, 26.4 mg/L ethiofencarb, 37.9 mg/L ethiofencarbsulfoxide, and 0.9 mg/L ethiofencarbsulfone. Ethanol (0.26 g/100 mL), ethiofencarb, ethiofencarbsulfoxide, and ethiofencarbsulfone were also detected in urine.

The cytochrome P450 (P450) and flavin-containing monooxygenase (FMO) enzymes are the major oxidative enzymes in phase I metabolism. Many organophosphate and carbamate thioether compounds are excellent substrates for these enzymes. Stereoselective sulfoxidation of fenthion and methiocarb by human liver, kidney, and microsomes was investigated. A high level of stereoselectivity in the formation of fenthion +-sulfoxide was observed in kidney and intestinal microsomes. This activity was not inhibited by the P450 inhibitor 1-aminobenzotriazole but was dramatically reduced following mild heat treatment. In liver, fenthion was metabolized to its sulfoxide in a nonstereoselective manner, and the activity was sensitive to both 1-aminobenzotriazole and heat treatment. The carbamate pesticide methiocarb also was sulfoxidated with a high degree of stereoselectivity in human kidney microsomes. Human liver microsomes formed both stereoisomers in equal amounts. Sulfoxide formation in kidney was not inhibited by 1-aminobenzotriazole but was abolished in liver microsomes. Formation of methiocarb sulfoxides was not observed in intestinal microsomes. The relative contribution of FMO1 and FMO3 to the sulfoxidation of carbophenothion, demeton-O, ethiofencarb, fonofos, and methiocarb also was investigated by using baculovirus-expressed recombinant proteins. FMO1 showed the highest catalytic activity for all pesticides. This study indicates that FMO1 may have a bigger role in extrahepatic metabolism than previously thought.

Ethiofencarb is one of the carbamate compounds, which are, in general, less toxic than organophosphorus insecticides. This is due to their reversible acetylcholinesterase inhibition and relative inability to cross the blood-brain barrier. Generally, ethiofencarb is regarded to be of low toxicity (LD(50) > 200 mg/kg); however, severe poisoning and death are not uncommon. To our knowledge, no measurements of ethiofencarb and its metabolites in human postmortem whole blood have been published. We present here a case report of fatal ethiofencarb intoxication with quantitative analysis of ethiofencarb and its metabolites in ante- and postmortem blood. In addition, postmortem urine was collected and analyzed. A 56-year-old man, who worked as a gardener, was found in poor condition, sitting in his car seat. He had been vomiting. The man was admitted to the local hospital about 1 h later. At admission, he was conscious, but unable to speak clearly. His condition deteriorated, and he developed severe pulmonary edema. Resuscitation with atropine and adrenaline were attempted, but he died approximately 3 h after admission. The analysis of postmortem peripheral blood revealed 0.12 g/100 mL ethanol, 26.4 mg/L ethiofencarb, 37.9 mg/L ethiofencarbsulfoxide, and 0.9 mg/L ethiofencarbsulfone. Ethanol (0.26 g/100 mL), ethiofencarb, ethiofencarbsulfoxide, and ethiofencarbsulfone were also detected in urine.

The cytochrome P450 (P450) and flavin-containing monooxygenase (FMO) enzymes are the major oxidative enzymes in phase I metabolism. Many organophosphate and carbamate thioether compounds are excellent substrates for these enzymes. Stereoselective sulfoxidation of fenthion and methiocarb by human liver, kidney, and microsomes was investigated. A high level of stereoselectivity in the formation of fenthion +-sulfoxide was observed in kidney and intestinal microsomes. This activity was not inhibited by the P450 inhibitor 1-aminobenzotriazole but was dramatically reduced following mild heat treatment. In liver, fenthion was metabolized to its sulfoxide in a nonstereoselective manner, and the activity was sensitive to both 1-aminobenzotriazole and heat treatment. The carbamate pesticide methiocarb also was sulfoxidated with a high degree of stereoselectivity in human kidney microsomes. Human liver microsomes formed both stereoisomers in equal amounts. Sulfoxide formation in kidney was not inhibited by 1-aminobenzotriazole but was abolished in liver microsomes. Formation of methiocarb sulfoxides was not observed in intestinal microsomes. The relative contribution of FMO1 and FMO3 to the sulfoxidation of carbophenothion, demeton-O, ethiofencarb, fonofos, and methiocarb also was investigated by using baculovirus-expressed recombinant proteins. FMO1 showed the highest catalytic activity for all pesticides. This study indicates that FMO1 may have a bigger role in extrahepatic metabolism than previously thought.

A kinetic study of the hydrolysis of ethiofencarb (-ethylthio-o-tolyl methylcarbamate) in pure water and in aqueous solutions at pH 2, 6, 9 and 12 and at three different temperatures (4, 20 and 50(+/-1)degC) has been carried out using a gas chromatographic nitrogen-phosphorus detection method. The values of the first-order rate constants (k) for the degradation reaction were calculated. The values for k were found to be dependent on pH and temperature. No acid hydrolysis was observed in any case. Complete degradation of ethiofencarb was observed at pH 12 at all three temperatures; it was practically instantaneous at room temperature. Ethiofencarb was also completely degraded at pH 9 at 20 and 50degC, while in pure water (pH 6) degradation took place at 50degC but not at 20degC. Ethiofencarb was not degraded in pure water at lower temperatures and, due to the reversible nature of the reaction, at equilibrium about 80% of the pesticide remained undegraded at room temperature.