Metabolism in relation to mode of action of methylenedioxyphenyl synergists in houseflies

Sesamol as an inhibitor of growth and lipid metabolism in Mucor circinelloides via its action on malic enzyme

“…It was thought possible that the active breakdown product of sesamol, responsible for the inhibition of cell growth and effects on lipid metabolism, may contain a methylenedioxybenzene structure. Such compounds have long been recognized as being inhibitors of microsomal oxidases in mammalian and insect systems (21)(22)(23).…”

Mixed-function oxidase involvement in the biochemistry of insecticide synergists

“…The microsomal mixed-function oxidase (mfo) system (discussed in some detail later) probably carries out the initial oxidative attack in the metabolism of most synergists. This is known to be true based on tic, glc, and colorimetric studies with respect to: demethylenation of several MDP compounds (III, V-VII, IX, and XI-XIII) (Casida et al, 1966;Esaac and Casida, 1969;Kamienski and Casida, 1970;Kuwatsuka, 1969;Wilkinson and Hicks, 1969) ; TV-deethylation of SKF 525A (XV), Lilly 18947 (XVI) and related TV-alkyl compounds ; cleavage of an aryl 2-propynyl ether (XX) (Matthews and Casida, 1970a); cleavage of dipropyl paraoxon (XXIV) to p-nitrophenol (Nakatsugawa et al, 1968); and hydroxylation of TOCP (XXVI) (Eto, 1969). The mouse liver mfo system has little or no activity in cleaving thiocyanates such as XXX and XXXI; the major metabolic pathway for many organic thiocyanates involves reaction with glutathione 5-transferases to liberate hydrogen cyanide (Ohkawa and Casida, 1970).…”

“…Piperonyl butoxide-a-C14 (VI) is excreted by Madeira cockroaches in unidentified, water-soluble metabolites (Schmidt and Dahm, 1956). Houseflies metabolize pb ( -C14 and M-Cl4-DP) by several alternative pathways involving cleavage at a methylene group adjacent to each oxygen, yielding a variety of alcohol-, catechol-, and carboxylic acid metabolites which are excreted either without conjugation or as glycosides, but the glycine conjugate of 6-propylpiperonylic acid is not formed (Esaac and Casida, 1969). When a large pb dose is fed orally by capsule to dogs, it is excreted unchanged to the extent of 78-88% in the feces within 48 hr, the urine containing little more than trace amounts of pb on the basis of colorimetric analysis (Sarles and Vandegrift, 1952).…”

“…Sulfoxide (VII) metabolism is not well understood but it is known that M-C14-DP preparations of the two diastereoisomeric components (Kuwatsuka and Casida, 1965) are extensively converted to C1402 in mice but less so in houseflies, and that oxidation of the sulfoxide group to the sulfone occurs, in part, before excretion of the metabolites by flies (Casida et al, 1966(Casida et al, ,1968Esaac and Casida, 1969; Kamienski and Casida, 1970).…”

Unexpected Metabolic Reactions and Secondary Targets of Pesticide Action

“…CYP inhibitors increase the toxicity of many insecticides − by intention (synergists shown in Figure ) or inadvertent exposure (fungicidal ergosterol biosynthesis inhibitors). The most important insecticide synergist is piperonyl butoxide, 5A , with the methylenedioxy carbon as the critical site of CYP interaction. − Phosphorothionates generally require oxidative desulfuration for activation as insecticides. Dietholate, 5B , and analogues yield “sulfoxidized phosphorothionates” at the CYP’s catalytic site which inhibit these detoxifying enzymes. , Dietholate was developed on this principle as an extender to prolong herbicide action in soil by inhibiting microbial CYPs .…”