Inhibitors as synergists

Monooxvgenase Inhibitors as Synergists. Inhibitors of cytochrome P450 are used as preliminary diagnostic synergists ( ) to detect resistance based on a mechanism of... 

Herbicide resistance has evolved in a number of weed species to many herbicides as a result of more rapid CYP-dependent detoxification. Some examples are provided in Table I. Evidence for increased CYP activity in these populations has come from the use of specific CYP inhibitors as synergists and from identification of the hydroxylated products of herbicide detoxification. 

In the case of ions, the repulsive interaction can be altered to an attractive interaction if an ion of opposite charge is simultaneously adsorbed. In a solution containing inhibitive anions and cations the adsorption of both ions may be enhanced and the inhibitive efficiency greatly increased compared to solutions of the individual ions. Thus, synergistic inhibitive effects occur in such mixtures of anionic and cationic inhibitors . These synergistic effects are particularly well defined in solutions containing halide ions, I. Br , Cl", with other inhibitors such as quaternary ammonium cations , alkyl benzene pyridinium cations , and various types of amines . It seems likely that co-ordinate-bond interactions also play some part in these synergistic effects, particularly in the interaction of the halide ions with the metal surfaces and with some amines . 

The rare example of synergistic action of a binary mixture of 1-naphthyl-A-phcnylaminc and phenol (1-naphthol, 2-(l,l-dimethylethyl)hydroquinone) on the initiated oxidation of cholesterol esters was evidenced by Vardanyan [34]. The mixture of two antioxidants was proved to terminate more chains than both inhibitors can do separately ( > /[xj). For example, 1-naphtol in a concentration of 5 x 10 5 mol L-1 creates the induction period t=170s, 1 -naphthyl-A-phenylamine in a concentration of 1.0 x 10-4 mol L 1 creates the induction period t = 400s, and together both antioxidants create the induction period r = 770 s (oxidation of ester of pelargonic acid cholesterol at 7= 348 K with AIBN as initiator). Hence, the ratio fs/ZfjXi was found equal to 2.78. The formation of an efficient intermediate inhibitor as a result of interaction of intermediate free radicals formed from phenol and amine was postulated. This inhibitor was proved to be produced by the interaction of oxidation products of phenol and amine. 

Another class of cytochrome P-450 inhibitors, compounds with a monosubstituted acetylenic function, are well known for their potential as insecticide synergists (21) and some have already been reported to be active as JH biosynthesis inhibitors as well (19, 22). Ortiz de Montellano and Kunze (23) have shown that many ethynyl substrates cause the destruction of rat hepatic cytochrome P-450, when the prosthetic heme is alkylated during attempted metabolism of the triple bond. Such suicide substrates must bind to the enzyme and be catalytically acceptable thereby offering a potential for selectivity. In fact, selectivity of suicide substrates for particular molecular forms (isozymes) of hepatic... 

Hunt (H54) reported the possible existence of a synergistic enzyme, which potentiated activity of crystalline hog pepsin at pH 2. He considered the potentiating effect of dilution on gastric juice peptic activity to be due not to dilution of the inhibitor, as assumed by Bucher et al. (B41, B42), but to the additional effect of the synergist. 

Dowd, PI and Sparkes, T.C. (1987). Inhibition of trans-pcrmelhrin hydrolysis in Pseiubfitusiu ini tudens (Walker) and ase of inhibitors as pyrethruid synergists. 

Since OPs inhibit serine hydrolases such as AChE by phosphorylating them, it follows that OPs are potential inhibitors of all other serine hydrolases. This means that OPs can be used as synergists, notably for the pyrethroids that are detoxified by ester hydrolysis, and OP-containing mixture have proven successful in several cases (34.) The usefulness of these mixtures can be prolonged by using them in rotations with other mixtures and/or insecticides. 

Materials that are not eflfective inhibitors when used alone may nevertheless be able to function as synergists by reacting with an oxidized form of an antioxidant to regenerate it and thus prolong its effectiveness. For example, carbon black forms an effective combination with thiols, disulfides, and elemental sulfur, even though these substances may be almost completely ineffective alone under comparable conditions. Synergistic combinations from a variety of chain terminators and sulfur compounds have been reported. A widely used combination of stabilizers for polyolefins is 2,6-di-ferf-butyl-4-methylphenol (BHT) (Figure 1.41a) with dilauryl thiodipropionate (DLTDP) ... 

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. 

On occasion, the term synergism has been applied to inhibitor interaction based simply on the observation that inhibition by combined application of A and B exceeds that obtained by either A or B alone. The term synergism is also occasionally used in describing growth promoter interactions in which promotion by A plus B is greater than that obtained by A or B alone. According to accepted definitions, these would not qualify as synergistic interactions. 

Chromates have been the most widely used passivating inhibitors in coatings, although toxicity and carcinogenicity potential have prompted use of molybdates (zinc and calcium zinc) and zinc phosphate in their place in certain cases. Alkaline extenders, such as wollastonite, are used as synergists with passivators in some applications, apparently providing a beneficial pH buffering effect. 

On the basis of the above, it might be expected that compounds which function as inhibitors of P450-linked m/os offer potential for use as synergists for herbicides initially detoxified in weed species via microsomal hydroxylation. This appears to be the case. Thus, the enzyme-activated inhibitor (suicide substrate) ABT blocked the oxidation of chlortoluron and isoproturon in wheat and enhanced the toxicity of both herbicides. ABT was found to preferentially inhibit the ring-methyl oxidation versus N-demethylation of chlortoluron, but such selectivity was not observed in a study of the influence of this inhibitor on the fate of chlortoluron in... 

One approach to combating antibiotic resistance caused by P-lactamase is to inhibit the enzyme (see Enzyme inhibition). Effective combinations of enzyme inhibitors with P-lactam antibiotics such as penicillins or cephalosporins, result in a synergistic response, lowering the minimal inhibitory concentration (MIC) by a factor of four or more for each component. However, inhibition of P-lactamases alone is not sufficient. Pharmacokinetics, stability, ability to penetrate bacteria, cost, and other factors are also important in determining whether an inhibitor is suitable for therapeutic use. Almost any class of P-lactam is capable of producing P-lactamase inhibitors. Several reviews have been pubUshed on P-lactamase inhibitors, detection, and properties (8—15). 

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