Received for publication June 22, 2004.
Revised November 7, 2004.
Accepted for publication November 10, 2004.

Extrahepatic metabolism of carbamate and organophosphate thioether compounds by the FMO and P450 system

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 in 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 microsomes, fenthion was metabolized to its sulfoxide in a non-stereoselective manner and the activity was sensitive to both 1-aminobenzotriazole and heat treatment. The carbamate pesticide methiocarb also was S-oxygenated with a high degree of stereoselectivity in human kidney microsomes. Human liver microsomes formed methiocarb S-oxide 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 larger role in extrahepatic metabolism than previously thought.

Key words: cytochrome P450, extrahepatic drug metabolism, flavin-containing monooxygenase, human CYP enzymes