Flavin Adenine Dinucleotide—Dependent Monooxygenase: Its Role in the Sulfoxidation of Pesticides in Mammals

Hajjar, Nicolas P.; Hodgson, Ernest

doi:10.1126/science.7403873

Cited by 90 publications

(22 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Organophosphates are bioactivated by desulfuration of the phosphorothionate sulfur to produce the oxon, a metabolite that is orders of magnitude more potent in cholinesterase inhibition (Neal & Halpert, 1982;Jokanovic, 2001). FMO-dependent oxidation of the thioether moiety produces the sulfoxide, a pathway that represents detoxication compared to oxon production (Hajjar & Hodgson, 1980Kulkarni & Hodgson, 1984;Osimitz & Kulkarni, 1985;Tynes & Hodgson, 1985b;Kinsler et al, 1988Kinsler et al, , 1990Buronfosse et al, 1995;Hodgson et al, 1998;Usmani et al, 2004). Again, we have found human FMO2 to be very effective at S-oxygenation of the thioether of phorate and disulfoton (Henderson et al, 2004a), as has been previously shown for other FMO enzymes and for the mouse FMO2 (Karoly & Rose, 2001).…”

Section: Genetic Polymorphisms Of Flavin-containing Monooxygenasementioning

confidence: 99%

Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

Krueger

Williams

2005

Pharmacology & Therapeutics

504

444

View full text Add to dashboard Cite

Flavin-containing monooxygenase (FMO) oxygenates drugs and xenobiotics containing a "softnucleophile", usually nitrogen or sulfur. FMO, like cytochrome P450 (CYP), is a monooxygenase, utilizing the reducing equivalents of NADPH to reduce 1 atom of molecular oxygen to water, while the other atom is used to oxidize the substrate. FMO and CYP also exhibit similar tissue and cellular location, molecular weight, substrate specificity, and exist as multiple enzymes under developmental control. The human FMO functional gene family is much smaller (5 families each with a single member) than CYP. FMO does not require a reductase to transfer electrons from NADPH and the catalytic cycle of the 2 monooxygenases is strikingly different. Another distinction is the lack of induction of FMOs by xenobiotics.In general, CYP is the major contributor to oxidative xenobiotic metabolism. However, FMO activity may be of significance in a number of cases and should not be overlooked. FMO and CYP have overlapping substrate specificities, but often yield distinct metabolites with potentially significant toxicological/pharmacological consequences.The physiological function(s) of FMO are poorly understood. Three of the 5 expressed human FMO genes, FMO1, FMO2 and FMO3, exhibit genetic polymorphisms. The most studied of these is FMO3 (adult human liver) in which mutant alleles contribute to the disease known as trimethylaminuria. The consequences of these FMO genetic polymorphisms in drug metabolism and human health are areas of research requiring further exploration.

show abstract

Section: Genetic Polymorphisms Of Flavin-containing Monooxygenasementioning

confidence: 99%

Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

Krueger

Williams

2005

Pharmacology & Therapeutics

504

444

View full text Add to dashboard Cite

show abstract

“…Some of the drugs identified as FMO substrates include frequently prescribed drugs such as cimetidine, ketoconazole, ranitidine, perazine, and tamoxifen (Cashman et al, 1993;Chung et al, 2000;Hodgson et al, 2000). Environmental toxicants of concern due to potential bioactivation by FMO include numerous thioether-containing pesticides (Hajjar and Hodgson, 1980;Ziegler-Skylakakis et al, 1998). A few endogenous compounds for FMOs have also been identified, but the precise physiological role of each enzyme of the family is unclear (Elfarra, 1995).…”

mentioning

confidence: 99%

Identification of Novel Variants of the Flavin-Containing Monooxygenase Gene Family in African Americans

Furnes¹,

Feng²,

Sommer³

et al. 2003

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Sequence polymorphisms in enzymes involved in drug metabolism have been widely implicated in the differences observed in the sensitivity to various xenobiotics. The flavin-containing monooxygenase (FMO) gene family in humans catalyzes the monooxygenation of numerous N-, P-and S-containing drugs, pesticides, and environmental toxicants. Six genes (FMO1-6) have been identified so far, but the major alleles of FMO2 and FMO6 encode nonfunctional proteins due to a nonsense mutation and splice-site abnormalities, respectively. Data on structural variants exist for human FMO2 and 3, whereas very little is known about the other FMO genes. FMO1-6 were scanned in 50 individuals of African-American descent using the method, detection of virtually all mutationssingle-strand conformational polymorphism. A total of 49 sequence variants were identified in a total 1.35 megabases of scanned sequence, of which 29 were variants affecting protein structure or expression. Some of these are expected to affect the activity of the protein, including a nonsense mutation in FMO1 (R502X) and missense mutations in FMO1 (I303T), FMO4 (E339Q), and FMO5 (P457L) that occur in highly conserved amino acids. Additional deleterious substitutions in FMO2 (del337G) and FMO6 (Q105X) were also identified. Multiple structural variants in the FMO gene family were observed in this African-American sample. Some of the substitutions identified in this study might be useful markers in future association studies assessing sensitivity to environmental toxicants and common disease.

show abstract

“…FMO catalyzes the oxygenation of nucleophilic nitrogen, sulfur, phosphorous, and selenium atoms in a multitude of structurally diverse compounds [19]. In this study, deprenyl and pargyline were found to be typical tertiary amines, and they were metabolized strongly by porcine liver FMO, being converted quantitatively to N-oxides [20].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine metabolic activity of porcine FAD‐containing monooxygenase by selective monoamine oxidase‐B inhibitors

Ichikawa

1995

FEBS Letters

View full text Add to dashboard Cite

The MPTP metabolic activity of porcine FAD-containing monooxygenase (FMO) (EC 1.14.13.8) was inhibited considerably by deprenyl and pargyline, selective MAO-B inhibitors, and they showed typical competitive inhibition. Deprenyl and pargyline, amine derivatives were also examined as to whether they are substrates for the FMO. It was found that deprenyl and pargyline are excellent substrates for the FMO. The K i and K m values of deprenyl and pargyline for the FMO are 14 pM and 9 pM, and 14.3 pM and 11.6 pM, at pH 8.0 and 25°C, respectively.Key words." FAD-containing monooxygenase; Monoamine oxidase-B inhibitor; Deprenyl; Pargyline [6]. The optical spectra of FMO are shown in Fig. 1, and the purified FMO gave a single protein band on SDS-PAGE (Fig. 2). Enzyme assay and kinetic parametersThe enzymatic activity was determined optically and aerobically by measuring the decrease in absorbance at 340 nm due to the oxidation of NADPH in the presence of a substrate. The reaction mixture comprised FMO (0.2 nmol), 0.1 M K-phosphate buffer, pH 8.0, at 25°C, and appropriate amounts of NADPH and 10 ~M to 600 ¢tM substrate, in a final volume of 1 ml. The reaction mixture was put into a cuvette of 1 cm light path and then the endogenous rate of the absorbance change at 340 nm was recorded for 5 rain at 25°C before addition of the substrate. After the addition of the substrate, the rate of the absorbance change was measured for 5 rain at 25°C, the endogenous rate being subtracted. For investigation of a reaction with a sequential Bi Bi mechanism, the Km, Vmax and K~ values of FMO for deprenyl and pargyline can be determined by means of Lineweaver-Burk plots [9].

show abstract

Flavin Adenine Dinucleotide—Dependent Monooxygenase: Its Role in the Sulfoxidation of Pesticides in Mammals

Cited by 90 publications

References 12 publications

Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

Identification of Novel Variants of the Flavin-Containing Monooxygenase Gene Family in African Americans

Inhibition of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine metabolic activity of porcine FAD‐containing monooxygenase by selective monoamine oxidase‐B inhibitors

Contact Info

Product

Resources

About