Role of human flavin-containing monooxygenases in the sulfoxidation of [ 14 C]aldicarb Daniel Schlenk, a, * John R. Cashman, b Cathy Yeung, c Xiaofei Zhang, a and Allan E. Rettie c a Department of Environmental Sciences, Environmental Toxicology Program, University of California, Riverside, CA 92521, USA b Human BioMolecular Research Institute, San Diego, CA, USA c Department of Medicinal Chemistry, University of Washington, USA Received 30 January 2002; accepted 20 March 2002 Abstract Biotransformation of the carbamate insecticide aldicarb to aldicarb sulfoxide has been shown to sig- nificantly increase its anticholinesterase activity. However, it is unclear what enzymes are responsible for this bioactivation. In this study, 51 human liver microsome samples were prepared and [ 14 C]aldicarb S- oxygenation was examined in vitro under saturating substrate incubations (200 lM). NADPH-catalyzed S- oxygenation activities were highly variable and observed in only 12 of 51 samples with a mean value of 0:034  0:17 nmol=min=mg of microsomal protein. Coincubation with 0.1% lubrol to inhibit contributions of cytochrome P450 failed to alter S-oxygenation activities (0:036  0:26 pmol=min=mg). Benzydamine N- oxygenation was also examined and was 2:57  1:66 nmol=min=mg and observed in all samples. Flavin- containing monooxygenase (FMO)3 content was determined in all samples and showed a significant correlation with benzydamine N-oxygenation (r 2 ¼ 0:41), but FMO3 did not correlate with [ 14 C]aldicarb S- oxygenation. Incubations of [ 14 C]aldicarb with five human recombinant flavin-monooxygenase isoforms indicated catalysis by FMO1  FMO3 with no activity detected from FMO2, FMO4, or FMO5. These results indicated limited hepatic biotransformation of [ 14 C]aldicarb in human liver microsomes, but sug- gests other tissues may be more important such as fetal liver, the intestine or kidney that possess significant levels of FMO1. Ó 2002 Elsevier Science (USA). All rights reserved. 1. Introduction Aldicarb [2-methyl-2-(methylthio) propanal O- (methylamino) carbonyl oxime; Temik] is a car- bamate insecticide and nematocide used heavily in the Southeastern United States [1]. As an insecti- cide, it ranks fifth in pounds applied and seventh in total acreage used as an insecticide within the United States [2]. There have been several docu- mented cases of human poisoning with aldicarb indicating cholinergic overload and acute periph- eral nervous system dysfunction when consumed in excessive concentrations [3,4]. A reversible inhibitor of acetyl and butyryl cholinesterases, aldicarb undergoes significant transformation in mammalian organisms [5]. Hy- drolysis of aldicarb catalyzed by other esterases produces nitrile and oxime metabolites which are Pesticide Biochemistry and Physiology 73 (2002) 67–73 www.academicpress.com * Corresponding author. Fax: +909-787-3993. E-mailaddress: daniel.schlenk@ucr.edu (D. Schlenk). 0048-3575/02/$ - see front matter Ó 2002 Elsevier Science (USA). All rights reserved. PII:S0048-3575(02)00013-5