Methylenedioxyphenyl compounds

In the reduced state, cytochromes P-450 may also bind certain ligands to give particular difference spectra. The most well known is that which occurs when carbon monoxide binds giving an absorption maximum at 450 nm. A type III spectrum gives two peaks at 430 and 455 nm after binding of certain compounds such as ethyl isocyanide or methylenedioxyphenyl compounds to the reduced enzyme. The latter form stable complexes with the enzyme and are also inhibitors. 

Certain methylenedioxyphenyl compounds such as safrole (84) bind to and inhibit cytochrome P450, probably via interaction of a carbene formed from the methylene group and... 

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],... 

Microsomal monooxygenase inhibitors that form stable inhibitory complexes with CYP, such as SKF-525A, piperonyl butoxide and other methylenedioxyphenyl compounds, and amphetamine and its derivatives, can be readily investigated in this way because the microsomes isolated from pretreated animals have a reduced capacity to oxidize many xenobiotics. 

Marcus. CJ.E3., Murray. M., Wang, C. and Wilkinson. C-E. (1986). Methylenedioxyphenyl compounds as inducers of cytochrome P450 and moilooxygenase activity in the Southern armvworm iSpadoptera endania) and the rat. Pestic. Btochern. Physiol. 26. 316-322. 

The methylenedioxy derivative can act in this way as the alternative substrate of the enzyme performing the microsomal hydroxylation, but the catechol formed may also contribute to the effect (Moore and Hewlett, 1958 Metcalf et al., 1966 Casida, 1970 Casida et al., 1966 Hennessy, 1965 1969 Hennessy and Whalen, 1966 Kuwatsuka, 1970). However, this does not explain the strength and duration of synergism produced by methylenedioxyphenyl compounds. Experimental results of Franklin (1974) indicate that during oxidative metabolism these compounds form an intermediate which strongly binds to cytochrome P-450 and thereby prevents further participation of the enzyme in oxidative metabolism. 

Additional methylenedioxyphenyl compounds have been S5mthesized and their human isoform selectivity as mechanism-based inactivators evalu-ated. Their inactivating potential depends on the side-chain structure, with bulky side chains such as 1,4-benzothiazine inactivating some P450 enzymes but not others. ... 

Interactions of methylenedioxyphenyl compounds with cytochrome P-450 and effects on microsomal oxidation. In E. Hodgson, J.R. Bend, and R.M. Philpot (eds.). Reviews in Biochemical Toxicology, Vol. 6. Elsevier, Amsterdam, pp. 27-63. 

Elcombe, C.R., J.W. Bridges, R.H. Nimmo-Smith, and J. Werringloer (1975). Cumene hydroperoxide-mediated formation of inhibited complexes of methylenedioxyphenyl compounds with cytochrome P-450. Biochem. Soc. Trans. 3, 967-970. 

Dahl, A.R. and E. Hodgson (1979). The interaction of aliphatic analogs of methylenedioxyphenyl compounds with cytochromes P-450 and P-420. Chem. Biol. Interact. 27, 163-175. 

Cook, J.C. and E. Hodgson (1983). Induction of cytochrome P-450 by methylenedioxyphenyl compounds Importance of the methylene carbon. Toxicol. Appl. Pharmacol. 68, 131-139. 

Generation of carbon monoxide during the microsomal metabolism of methylenedioxyphenyl compounds. Biochem. Pharmacol. 29, 1113-1122. 

Nakajima M, Suzuki M, Yamaji R, et al. Isoform selective inhibition and inactivation of human cytochrome P450s by methylenedioxyphenyl compounds. Xenobiotica 1999 29 1191-1202. 

Murray M. Mechanisms of inhibitory and regulatory effects of methylenedioxyphenyl compounds on cytochrome P450-dependent drug oxidation. Curr Drug Metab 2000 1 67-84. 

Kumagai Y, Wickham KA, Schmitz DA, Cho AK (1991) Metabolism of methylenedioxyphenyl compounds by rabbit liver preparations. Participation of different cytochrome P450 isozymes in the demeth-ylenation reaction. Biochem Pharmacol 42 1061-1067... 

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