S-oxygenation of the thioether organophosphate insecticides phorate and disulfoton by human lung flavin-containing monooxygenase 2.
Phorate and disulfoton are organophosphate insecticides containing three oxidizable sulfurs, including a thioether. Previous studies have shown that only the thioether is oxygenated by flavin-containing monooxygenase (FMO) and the sole product is the sulfoxide with no oxygenation to the sulfone. The major FMO in lung of most mammals, including non-human primates, is FMO2. The FMO2*2 allele, found in all Caucasians and Asians genotyped to date, codes for a truncated, non-functional, protein (FMO2.2A). Twenty-six percent of individuals of African descent and 5% of Hispanics have the FMO2*1 allele, coding for full-length, functional protein (FMO2.1). We have here demonstrated that the thioether-containing organophosphate insecticides, phorate and disulfoton, are substrates for expressed human FMO2.1 with Km of 57 and 32 microM, respectively. LC/MS confirmed the addition of oxygen and formation of a single polar metabolite for each chemical. MS/MS analysis confirmed the metabolites to be the respective sulfoxides. Co-incubations with glutathione did not reduce yield, suggesting they are not highly electrophilic. As the sulfoxide of phorate is a markedly less effective acetylcholinesterase inhibitor than the cytochrome P450 metabolites (oxon, oxon sulfoxide or oxon sulfone), humans possessing the FMO2*1 allele may be more resistant to organophosphate-mediated toxicity when pulmonary metabolism is an important route of exposure or disposition.
Henderson
Marilyn C
MC
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, USA.
Krueger
Sharon K
SK
Siddens
Lisbeth K
LK
Stevens
Jan F
JF
Williams
David E
DE
D000818:Animals; D004222:Disulfoton / Q000378:metabolism*; D006801:Humans; D007306:Insecticides / Q000378:metabolism*; D008168:Lung / Q000201:enzymology*; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000378:metabolism*; D010702:Phorate / Q000378:metabolism*; D011817:Rabbits
D007306:Insecticides; D004222:Disulfoton; D010702:Phorate; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)