Abstract
Biotransformation of the carbamate insecticide aldicarb to aldicarb sulfoxide has been shown to significantly 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 [ 14C]aldicarb S-oxygenation was examined in vitro under saturating substrate incubations ( 200 μM ). 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=0.41), but FMO3 did not correlate with [ 14C]aldicarb S-oxygenation. Incubations of [ 14C]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 [ 14C]aldicarb in human liver microsomes, but suggests other tissues may be more important such as fetal liver, the intestine or kidney that possess significant levels of FMO1.
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