Methylenedioxyphenyl synergists

The two most important difference spectra of reduced CYP are the well-known CO spectrum, with its maximum at or about 450 nm, and the type III spectrum, with two pH-dependent peaks at approximately 430 and 455 nm. The CO spectrum forms the basis for the quantitative estimation of CYP. The best-known type III ligands for CYP are ethyl isocyanide and compounds such as the methylenedioxyphenyl synergists and SKF 525A, the last two forming stable type III complexes that appear to be related to the mechanism by which they inhibit monooxygenations. 

Although examples are known in which synergistic interactions take place at the receptor site, the majority of such interactions appear to involve the inhibition of xenobiotic-metabolizing enzymes. Two examples involve the insecticide synergists, particularly the methylenedioxyphenyl synergists, and the potentiation of the insecticide malathion by a large number of other organophosphate compounds. 

Kamierski, F.X. and Casida. J.R. f 1970). Importance of demelhylation in the melabo-lisin in vivo and in vitro of methylenedioxyphenyl synergists and related compounds in mammals, BUxhtm. Phanmu-ot. 19, 91-112. 

The methylenedioxyphenyl synergists have the following general structure ... 

Cinnamyl—sesamol ethers, eg (35), are useful as insect chemosterilants (111). 3,4-Methylenedioxyphenyl-3-halo-2-propynyl ethers (36, X = halogen) are synergists for carbamate insecticides (112). HaloaLkyl or haloalkenyl ethers, eg (37), show acaricidal and insect juvenile hormone activity (113). The first total synthesis of gibbereUic acid was from 2-methoxy-6-aLkoxyethyl-l,4-benzoquinone, a derivative of hydroxyhydroquinone (114). 

The definition of a poison, or toxicant, also involves a qualitative biological aspect because a compound, toxic to one species or genetic strain, may be relatively harmless to another. For example, carbon tetrachloride, a potent hepatotoxicant in many species, is relatively harmless to the chicken. Certain strains of rabbit can eat Belladonna with impunity while others cannot. Compounds may be toxic under some circumstances but not others or, perhaps, toxic in combination with another compound but nontoxic alone. The methylenedioxyphenyl insecticide synergists, such as piperonyl butoxide, are of low toxicity to both insects and mammals when administered alone but are, by virtue of their ability to inhibit xenobiotic-metabolizing enzymes, capable of causing dramatic increases in the toxicity of other compounds. 

Irreversible inhibition, which is much more important toxicologically, can arise from various causes. In most cases the formation of covalent or other stable bonds or the disruption of the enzyme structure is involved. In these cases the effect cannot be readily reversed in vitro by either dialysis or dilution. The formation of stable inhibitory complexes may involve the prior formation of a reactive intermediate that then interacts with the enzyme. An excellent example of this type of inhibition is the effect of the insecticide synergist piperonyl butoxide (Figure 9.6) on hepatic microsomal monooxygenase activity. This methylenedioxyphenyl compound can form a stable inhibitory complex that blocks CO binding to P450 and also prevents substrate oxidation. This complex results from the formation of a reactive intermediate, which is shown by the fact that the type of inhibition changes from competitive to irreversible as metabolism, in the... 

Ethanol and a number of other chemicals, including acetone and certain imidazoles, induce CYP2E1. Piperonyl butoxide, isosafrole, and other methylenedioxyphenyl compounds are known to induce CYP1A2 by a non-Ah receptor-dependent mechanism. Peroxisome proliferators, including the drug, clofibrate, and the herbicide synergist tridiphane induce a CYP4A isozyme that catalyzes the -oxidation of lauric acid. 

It is apparent from extensive reviews of the induction of monooxygenase activity by xenobiotics that many compounds other than methylenedioxyphenyl compounds have the same effect. It may be that any synergist that functions by inhibiting microsomal monooxygenase activity could also induce this activity on longer exposure, resulting in a biphasic curve as described previously for methylenedioxyphenyl compounds. This curve has been demonstrated for NIA 16824 (2-methylpropyl-2-propynyl phenylphosphonate) and WL 19255 (5,6-dichloro-l,2,3-benzothiadiazole), although the results were less marked with R05-8019 [2,(2,4,5-trichlorophenyl)-propynyl ether] and MGK 264 [A-(2-ethylhexyl)-5-norbomene-2,3-dicarboximide],... 

Inhibition of JH III biosynthesis In vitro. All three acetylenic compounds were significantly better Inhibitors of JH biosynthesis than precocene II under similar Incubation conditions (Fig. 4). Compound 2 was the best Inhibitor tested here, with an I50 of 16 pM, more than 25 times better than precocene II. Whether this better performance as an Inhibitor Is due to a closer structural analogy with the natural substrate of the epoxidase or whether it Is a consequence of the presumed difference In the mode of action (Irreversible Inhibition of the epoxidase for cytotoxicity of precocene epoxide eventually resulting In decreased JH biosynthetic rate for 1) Is not presently known. The Insecticide synergist (4) proved to be about 7 times better than precocene II. Its activity as an inhibitor of JH biosynthesis by D. punctata CA is similar to that of 3 and the methylenedioxyphenyl analog of JH (Ro 20-3600). 

Bowman, M,C, and Beroza, M, 1967). Spectra and analyses of insecticide synergists and related compounds containing the methylenedioxyphenyl group hy xpectro-pbolofluoromelry (SPF) and spectrophotophn.sphorimelrv (SPP). Residin Rev. 17, 1-22. 

Jaffe H, Fujii K, Sengupta M, Guerin H, Epstein SS. In vivo inhibition of mouse liver microsomal hydroxylating systems by methylenedioxyphenyl insecticidal synergists and related compounds. Life Sci 1968 7 1051-62. 

Methylenedioxyphenyl derivatives, primarily sesamex, can strongly synergise the action of aldrin, presumably by the inhibition of microsomal enzymes responsible for biodegradation (Brooks and Harrison, 1964 Brooks, 1966 1968 Sun et al., 1967 Casida, 1970 Khan et al., 1970). From the viewpoint of environmental hygiene this may become important, because the application of synergists may enable the use of analogues acting in the same way as compounds used at present, but which are more rapidly decomposed (Hennessy, 1969). 

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