Mixed-function oxidase inhibitor

Attempts to diminish the overall metabolism of trichloroethylene might be useful (e.g., hypothermia, mixed-function oxidase inhibitors, competitive inhibitors of trichloroethylene metabolism [i.e., P-450 substrates]), if instituted soon enough after trichloroethylene exposure. Catecholamines (especially beta agonists) act in concert with trichloroethylene, increasing the risk of cardiac arrhythmias. Hence, catecholamines should be administered to patients only in the lowest efficacious doses and for certain limited presentations of trichloroethylene poisoning. Ethanol should also be avoided because concurrent exposure to trichloroethylene and ethanol can cause vasodilation and malaise and may potentiate central nervous system depression at high dosage levels of either compound. 

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... 

Koiwai, A., and T. Kisaki. Mixed function oxidase inhibitors protect plants from ozone injury. Agric. Biol. Chem. 37 2449-2450, 1973. 

Support for this is found in the substantially greater octopa-minomimetic activity of DCDM compared to chlordimeform (20) and the observation that mixed function oxidase inhibitors, e.g. piperonyl butoxide and sesamex, strongly antagonized the toxicity of chlordimeform to the southern cattle tick larvae and synergized the toxicity of DCDM (21). Therefore, chlordimeform may be considered to be a propesticide of DCDM. 

In addition, oral administration of 1- C-2-hexanone to humans or rats results in the appearance of CO in the expired breath (DiVincenzo et al. 1977, 1978), indicating oxidation/cleavage of the alpha carbon. Administration of SKF525A (a mixed function oxidase inhibitor) to rats before oral administration of 2-hexanone resulted in a marked decrease in the excretion of respiratory CO for the first 4 hours after administration, followed by a marked increase at 4-8 and 12-24 hours. This suggests that this oxidative step is mediated by a microsomal mixed function oxidase system (DiVincenzo etal. 1977). 

Ndifor AM, Howells RE, Bray PG, Ngu JL, Ward SA. Enhancement of drug susceptibihty in Plasmodium falciparum in vitro and Plasmodium berghei in vivo by mixed-function oxidase inhibitors. Antimicrob Agents Chemother 1993 37(6) 1318-23. 

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). 

The mixed-function oxidase inhibitors aminobenzotriazole and piperonyl butoxide can synergize herbicide activity in resistant Lolium growing in a hydroponic system. This indicates that at least one aspect of cross-resistance in Lolium rigidum may be related to enhanced metabolic activity of mixed-function oxidazes acting to detoxify herbicides. We are now concentrating on direct studies of herbicide metabolism in resistant biotypes. 

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). 

One of the most commonly found mid-chain hydroxylated components is dihydroxyhexadecanoic acid, which has hydroxyl moieties at C-10, C-9, C-8 or C-7, and on C-16 (232, 243, 244). A crude cell-free preparation from excised epidermis of V. faba catalyzed C-10 hydroxylation of 16-hydroxyhexadecanoic acid (473). This hydroxylation reaction was also catalyzed by the endoplasmic reticulum fraction from the embryonic shoots of K faba. This preparation required O2 and NADPH to catalyze mid-chain hydroxylation and the activity was inhibited by the typical mixed-function oxidase inhibitors and also by CO (427). The inhibition by CO was photoreversible, as expected of a cytochrome P450 hydroxylase. 

Cytochrome P450 2C19, also termed S-mephenytoin hydroxylase, is a mixed-function oxidase localized in the endoplasmic reticulum which is responsible for the biotransformation of S-mephenytoin, some barbiturates, almost all proton pump inhibitors such as omeprazole, diazepam and others. 

Pawar SS, Fawade MM. 1978. Alterations in the toxicity of thiodemeton due to the pretreatment of inducers, substrates and inhibitors of mixed function oxidase system. Bull Environ Contam Toxicol 20 805-810. 

Table II summarizes the results together with the detailed experimental conditions. As is evident, metabolic activities were detectable in these 3 aquatic species, but the rate was far lower as compared with mammalian hepatic enzume preparations, and the oxidative activities in snail were particularly low although the possibility was not ruled out of the presence of inhibitors of mixed-function oxidases in the fractions. The O-demethylation reaction proceeds extremely slowly in the enzyme preparation of aquatic animals, at less than one hundredth that of mammals.

Several studies have been conducted to assess factors which influence the toxicity of hexachlorobutadiene. Most of these studies have involved effects of mixed function oxidase activity (MFO) on renal toxicity. The administration of MFO inhibitors including SKF-525A (Lock and Ishmael 1981) and piperonyl butoxide (Davis 1984 Hook et al. 1982) did not alter... 

Kostyuk VA, Potapovich Al. 1991. Damage of rat liver microsomal mixed function oxidase system by carbon tetrachloride in wVo study with selective inhibitor of lipid peroxidation. Biochemistry International 25 349- 353. 

Woo, Y.T., Argus, M.F. Arcos, J.C. (1977b) Metabolism in vivo of dioxane effect of inducers and inhibitors of hepatic mixed-function oxidases. Biochem. Pharmacol., 25, 1539-1542 Woo, Y.T., Argus, M.F. Arcos, J.C. (1978) Effect of mixed-function oxidase modifiers on... 

Kerklaan, P.R.M.. Bouter, S., Zijlstra, J. A. Mohn, GR. (1986) The effect of mixed-function oxidase and amine oxidase inhibitors on the activation of dialkylnitrosamines and 1,2-dimethylhydrazine to bacterial mutagens in mice. J. Cancer Res. din. Oncol., Ill, 196-202... 

Correct choice = A. Rifampin induces the hepatic mixed function oxidases that metabolize warfarin. Platelet inhibitors, such as aspirin, increase the anticoagulant effect of warfarin. Phenylbutazone can transiently increase the level of free warfarin by displacing it from the plasma albumin binding site. Cimetidine inhibits warfarin metabolism and causes potentiation of the anticoagulant. Disulfiram inhibits warfarin metabolism. 

Most of these studies have established that the enzyme is located in the mitochondrial fraction of tissue homogenates, although the enzyme in the fat body and Malpighian tubules of Locusta is reportedly associated with the microsomal fraction (30). All studies concur that the enzyme is a cytochrome P-450-mediated mixed-function oxidase and its requirements for NADPH and 02 and sensitivity to inhibitors such as carbon monoxide, metyrapone, etc., support this conclusion. As yet, there are no reports as to whether the enzyme is associated with an iron sulfur protein similar to the adrenodoxin of the mammalian mitochondrial steroid... 

The renal cytochrome P-450 enzyme system is involved in oxidative reactions in which an atom of molecular oxygen is inserted in an organic molecule. The flavoprotein NADPH-cytochrome P-450 reductase is an essential component of the mixed-function oxidase systems (MFO). Microsomal membranes appear to be particularly subject to attack by reactive oxygen radicals due to their high content of unsaturated fatty acids and the presence of the cytochrome P-450 system [40]. Cephaloridine-induced peroxidation of membrane lipids is decreased by the cytochrome P-450 inhibitor cobalt chloride [31], suggesting a role for a cytochrome P-450 reductase in the P-lactam-induced generation of reactive oxygen species and subsequent peroxidation products. 

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