Use of aquatic organisms as models to determine the in vivo contribution of flavin-containing monooxygenases in xenobiotic biotransformation.

In an attempt to understand the evolution and role of flavin-containing monooxygenases (FMOs) in xenobiotic biotransformation by aquatic organisms, a survey of hepatic FMO activity (N,N-dimethylaniline N-oxidase and thiourea oxidase) was performed in one brackish water fish and 17 species of freshwater fish, one of which was anadromous. Only hepatic microsomes from the brackish water medaka (Oryzia latipes), the freshwater centrarid Lepomis macrochirus, and the anadromous rainbow trout (Oncorhynchus mykiss) consistently demonstrated FMO activity. Previous studies in trout have shown that the carbarmate insecticide, aldicarb, is bioactivated through an FMO-catalyzed S-oxidation. The toxicity of aldicarb was examined in O. mykiss and one of the species that did not show measurable FMO activity or protein, the channel catfish (Ictalurus punctatus). Rainbow trout were approximately 100 times more sensitive to aldicarb toxicity compared with channel catfish after a 96-hour waterborne exposure or 24 hours following intraperitoneal injection. However, rainbow trout were only 10 times more sensitive to aldicarb S-oxide, the bioactivated metabolite, than catfish 24 hours following intraperitoneal injection. Elimination profiles of injected aldicarb in both species fit a two-compartment model, but half-lives were significantly different between each species. Aldicarb and metabolites were rapidly cleared from trout (respective alpha and beta half-lives being 3 and 28 hr), while half-lives in catfish were significantly longer (alpha and beta half-lives being 16 and 140 hr). The major metabolite from catfish after 24 hours was aldicarb sulfone, which was 9.3% of the total dose. In trout, aldicarb sulfoxide was the major metabolite (7.6% of total dose) without any measurable sulfone. Because cytochrome P450 monooxygenases also perform the S-oxidation of aldicarb and differences in aldicarb disposition exist, future experiments will attempt to transfect catfish with rainbow trout FMO cDNA in order to determine the role of FMOs in aldicarb biotransformation and toxicity.