Synergists mixed-function oxidases

In an effort to characterize further the metabolism of DEHP by trout, the effect of the mixed function oxidase inhibitor, piperonyl butoxide, upon the metabolism of DEHP by these trout liver fractions and serum was examined. Because of the use of piperonyl butoxide as an insecticide synergist, it is possible that fish might be exposed to this chemical in the environment. The data in Table VII show that piperonyl butoxide inhibited overall metabolism of DEHP by liver homogenates and microsomes whether NADPH was added or not. The hydrolysis of DEHP by serum was also blocked by piperonyl butoxide and although not shown, this was also the case with liver cytosol. These latter results were surprising because piperonyl butoxide has been known as a mixed function oxidase inhibitor only, and would not be expected... 

Synergists That Inhibit Mixed-function Oxidases... 

Casida, J.E., Mixed-function oxidase involvement in the biochemistry of insecticide synergists, /. Agric. Food Client., 18, 753,1970. 

Skrmijarie-Spoljar, M., Mathews, H.H., Engel, J.I.. and Casida. J.IU (197 I). Response of hepatic microsomal mixed-function oxidases to v-ariuus types of insecticide cliemical synergists administered to mite. Biockem. Phnnuucol 20. 1607-1618. 

The relative ease in which PBO is oxidized may account for ils known aelion as a mixed function oxidase inhibitor. In more stable analogues of PBO the alkoxy side chain is replaced with a more oxidatively stable n-alkyl side chain of equal length, which greatly diminishes the synergistic effect. The same is true of other synergists such as Tropital (Maciver, 1966). 

An integrated approach to the use of ADME studies in conjunction with extensive toxicity testing of PBO has been crucial for the development of an optimal regulatory position for the compound. The toxieokinetic studies explain how PBO is metabolized by the body, and how this process in turn leads to its efficacy as synergist for insecticides and also to its activity as a mixed function oxidase inducer in mammals. The latter property accounts for the principal toxicological hndings seen with the compound, namely liver tumours in mice and weak thyroid effects in rats. 

There has been some work suggesting that some synergists, including PBO, may have morphogenic effects similar to juvenile hormone analogues (Bowers. 1968), This has not been substantiated (Red fern et at.. 1969) and it is most likely thaL Lite effect is due to mixed function oxidase inhibition interfering with the terminal steps in juvenile hormone synthesis (Staai. 1986). 

Safrole (25) and isosafrole were once important as the flavoring for root beer. These compounds are present in the plant extracts used to make this beverage. By the 1950s, however, most root beer was flavored with synthetically derived safrole. Both safrole and isosafrole were shown to be weakly carcinogenic and now have been banned for this purpose (Fishbein et al., 1967). These compounds have a methylenedioxy structure and are known to inhibit mixed-function oxidase enzymes. Two compounds of similar structure, piperonal (26) (naturally occurring) and piperonyl bu-toxide (27) (synthetic) are mixed function oxidase inhibitors and are used as synergists for insecticides such as pyrethrins, rotenoids, and Sevin (a carbamate insecticide) (Fishbein et al., 1967). 

Several pesticides and other xenobiotics are metabolized in plants by mixed-function oxidases which are cytochrome P-450-dependent [28]. Inhibitors of such enzymes might therefore serve as synergists of herbicides or other crop protection compounds which are oxidatively degraded. Therefore, it has been logical to test whether the growth retardants believed to be oxygenase inhibitors would interfere with xenobiotic metabolism. Under in vitro conditions it has indeed been observed that tetcyclacis at relatively low concentrations inhibits the metabolism of the herbicide chlortoluron [10]. Similarly, the herbicidal activity of bentazon could be enhanced by tetcyclacis which, most likely, reduced its oxidative inactivation [18]. Further studies will, however, be required to find out whether such effects can be used under practical conditions. 

---