16709-30-1

Usage

InChI:InChI=1/C12H13NO4/c1-12(2)10(14)7-5-4-6-8(9(7)17-12)16-11(15)13-3/h4-6H,1-3H3,(H,13,15)

Upstream product

• 55285-14-8 carbosulfan 
• 1563-66-2 2,3-dihydro-2,2-dimethyl-7-benzofuranol methylcarbamate 

Downstream Products

• 19019-30-8 hydroxymethylcarbamic acid 2,2-dimethyl-3-oxo-2,3-dihydrobenzofuran-7-yl ester 
• 17781-16-7 2,3-dihydro-3-oxo-2,2-dimethylbenzofuran-7-ol 
• 16655-82-6 3-Hydroxycarbofuran 

Relevant academic research and scientific papers

Metabolism of carbosulfan II. Human interindividual variability in its in vitro hepatic biotransformation and the identification of the cytochrome P450 isoforms involved

This study aims to characterize interindividual variability and individual CYP enzymes involved in the in vitro metabolism of the carbamate insecticide carbosulfan. Microsomes from ten human livers (HLM) were used to characterize the interindividual variability in carbosulfan activation. Altogether eight phase I metabolites were analyzed by LC-MS. The primary metabolic pathways were detoxification by the initial oxidation of sulfur to carbosulfan sulfinamide ('sulfur oxidation pathway') and activation via cleavage of the nitrogen sulfur bond (N-S) to give carbofuran and dibutylamine ('carbofuran pathway'). Differences between maximum and minimum carbosulfan activation values with HLM indicated nearly 5.9-, 7.0, and 6.6-fold variability in the km, Vmax and CLint values, respectively. CYP3A5 and CYP2B6 had the greatest efficiency to form carbosulfan sulfinamide, while CYP3A4 and CYP3A5 were the most efficient in the generation of the carbofuran metabolic pathway. Based on average abundances of CYP enzymes in human liver, CYP3A4 contributed to 98% of carbosulfan activation, while CYP3A4 and CYP2B6 contributed 57 and 37% to detoxification, respectively. Significant correlations between carbosulfan activation and CYP marker activities were seen with CYP3A4 (omeprazole sulfoxidation), CYP2C19 (omeprazole 5-hydroxylation) and CYP3A4 (midazolam 1′-hydroxylation), displaying r2=0.96, 0.87 and 0.82, respectively. Activation and detoxification pathways were inhibited by ketoconazole, a specific CYP3A4 inhibitor, by 90-97% and 47-94%, respectively. Carbosulfan inhibited relatively potently CYP3A4 and moderately CYP1A1/2 and CYP2C19 in pooled HLM. These results suggest that the carbosulfan activation pathway is more important than the detoxification pathway, and that carbosulfan activation is predominantly catalyzed in humans by CYP3A4.

Chemical models of cytochrome P450 catalyzed insecticide metabolism. Application to the oxidative metabolism of carbamate insecticides

Cytochrome P450 (CP450) catalyzed oxidative metabolism of carbofuran (1), carbaryl (2), and pirimicarb (3) has been modeled using biomimetic oxidations catalyzed by iron(III) tetraarylporphyrins. Oxidation products of 1 were identified by comparison of HPLC retention times measured under standardized conditions for metabolites synthesized and characterized by 1H and 13C NMR spectroscopy. Comparison of product distributions to in vivo metabolic profiles revealed that the H2O2/meso- tetrakis(pentafluorophenyl)porphyrin iron(III) chloride [Fe(TF20PP)] system mimics the action of insect CP450s against carbofuran. The effectiveness of this system was further demonstrated by the biomimetic oxidation of other carbamate insecticides (2 and 3) monitored by HPLC/electrospray MS. The predictive power of this biomimetic model was compared to that of knowledgebased expert systems. Although similar models were recently applied in pharmaceutical research, the usefulness of this approach has first been demonstrated for the prediction of metabolic profiles of agrochemicals.