Extrahepatic metabolism of carbamate and organophosphate thioether compounds by the flavin-containing monooxygenase and cytochrome P450 systems.
Drug Metab Dispos. 2005 Feb; 33(2):214-8.DM

Abstract

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.

Authors+Show Affiliations

Furnes B

University of California, Riverside, 307 Science Laboratories I, Riverside, CA 92507, USA.

Schlenk D

No affiliation info available

MeSH

CarbamatesCytochrome P-450 Enzyme SystemHumansIntestinal MucosaIntestinesKidneyMicrosomesMicrosomes, LiverOrganophosphatesOxygenasesSulfides

Pub Type(s)

Comparative Study

Journal Article

Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15547051

Citation

Furnes, Bjarte, and Daniel Schlenk. "Extrahepatic Metabolism of Carbamate and Organophosphate Thioether Compounds By the Flavin-containing Monooxygenase and Cytochrome P450 Systems." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 33, no. 2, 2005, pp. 214-8.

Furnes B, Schlenk D. Extrahepatic metabolism of carbamate and organophosphate thioether compounds by the flavin-containing monooxygenase and cytochrome P450 systems. Drug Metab Dispos. 2005;33(2):214-8.

Furnes, B., & Schlenk, D. (2005). Extrahepatic metabolism of carbamate and organophosphate thioether compounds by the flavin-containing monooxygenase and cytochrome P450 systems. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 33(2), 214-8.

Furnes B, Schlenk D. Extrahepatic Metabolism of Carbamate and Organophosphate Thioether Compounds By the Flavin-containing Monooxygenase and Cytochrome P450 Systems. Drug Metab Dispos. 2005;33(2):214-8. PubMed PMID: 15547051.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Extrahepatic metabolism of carbamate and organophosphate thioether compounds by the flavin-containing monooxygenase and cytochrome P450 systems. AU - Furnes,Bjarte, AU - Schlenk,Daniel, Y1 - 2004/11/16/ PY - 2004/11/18/pubmed PY - 2005/6/2/medline PY - 2004/11/18/entrez SP - 214 EP - 8 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 33 IS - 2 N2 - 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. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/15547051/Extrahepatic_metabolism_of_carbamate_and_organophosphate_thioether_compounds_by_the_flavin_containing_monooxygenase_and_cytochrome_P450_systems_ DB - PRIME DP - Unbound Medicine ER -

Tags

Extrahepatic metabolism of carbamate and organophosphate thioether compounds by the flavin-containing monooxygenase and cytochrome P450 systems.Drug Metab Dispos. 2005 Feb; 33(2):214-8.DM