Mixed function oxidase system

Tyagi SR, Sing Y, Srivastava PK, et al. 1984. Induction of hepatic mixed function oxidase system by endosulfan in rats. Bull Environ Contam Toxicol 32 550-556. 

By enhancing the metabolism of trichloroethylene to its cytotoxic metabolites, compounds that induce the hepatic mixed-function oxidase system can potentiate the hepatotoxicity of trichloroethylene. 

Lipid-soluble xenobiotics are commonly biotra ns formed by oxidation in the drug-metabolizing microsomal system (DMMS). For each description below, choose the component of the microsomal mixed-function oxidase system with which it is most closely associated ... 

The answers are 34-g, 35-a, 36-d. (Katzung, pp 53—56J There are four major components to the mixed-function oxidase system (1) cytochrome P450, (2) NAD PH, or reduced nicotinamide adenine dinucleotide phosphate, (3) NAD PH—cytochrome P450 reductase, and (4) molecular oxygen. The figure that follows shows the catalytic cycle for the reactions dependent upon cytochrome P450. 

Peakall, D.B., R.J. Norstrom, A.D. Rahimtula, and R.D. Butler. 1986. Characterization of mixed-function oxidase systems of the nestling herring gull and its implications for bioeffects monitoring. Environ. Toxicol. Chem. 5 379-385. 

Hexachloroethane is metabolized by the mixed function oxidase system by way of a two-step reduction reaction involving cytochrome P-450 and either reduced nicotinamide adenine dinucleotide phosphate (NADPH) or cytochrome b5 as an electron donor. The first step of the reduction reaction results in the formation of the pentachloroethyl free radical. In the second step, tetrachloroethene is formed as the primary metabolite. Two chloride ions are released. Pentachloroethane is a minor metabolic product that is generated from the pentachloroethyl free radical. 

Liver necrosis is another concern following hexachloroethane exposure. Hexachloroethane is metabolized in the centrilobular area of the liver by way of the microsomal mixed function oxidase system. The relatively nonpolar pentachloroethyl free radical is an intermediate in this pathway. The reaction of the free radical with unsaturated lipids in the cellular or organelle membranes could contribute to hepatocyte damage and necrosis. 

Freudenthal, R., Leber, P., Emmerling, D., Kerchner, G. and Campbell, D. (1976). Characterization of the hepatic microsomal mixed-function oxidase system in miniature pigs. Drug Metab. Dispos. 4 25-27. 

Hartgrove RW Jr., Hundley SG, Webb RE. 1977. Characterization of the hepatic mixed function oxidase system in endrin-resistant and -susceptible pine voles. Pesticide Biochemistry and Physiology 7 146-153. 

Fawade MM, Pawar SS. 1978. Alterations in mixed function oxidase system during thiodemeton (o-o diethyl S-2(ethylthio) ethyl phosphorothioate) toxicity. Indian J Exp Biol 16 481-484. 

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. 

Molinate Metabolism in Carp Hepatic Mixed-function Oxidase System. Incubation of molinate with carp liver microsomes produced four major organosoluble metabolites (molinate sulfoxide, 3- and 4-hydroxy molinate, and keto HMI). Parameters affecting... 

Quantitation and Identification of 11>C-labeled Metabolites. In the iji vitro microsomal mixed-function oxidase system,... 

In water containing fish, 4-keto molinate constituted 36.8% of all organosoluble metabolites 4 days after molinate addition. However, in the in vitro microsomal mixed-function oxidase system 4-hydroxy molinate was a principal metabolite (14.3%) and 4-keto molinate represented only 0.16% of the total metabolites. Keto-HMI (2.71%) also constituted a substantial proportion of the identified metabolites. 

In mammals the cytochrome P-U50 mediated monooxygenase or mixed function oxidase system involved in the elimination of lipophilic environmental contaminants and other foreign compounds, has been implicated in the carcinogen activation process. There are several distinct variants of cytochrome P-U50 in mammalian tissues and there may be more than one form of this ubiquitous cytochrome also in fish. The significance of this lies in the fact that different forms of cytochrome P-U50 result in different metabolite patterns, which in turn may reflect on the carcinogenicity or toxicity of compounds being metabolized. 

Hepatic microsomal and solubilized mixed-function oxidase systems from the little skate, Baja erinacea, a marine elasmobranch. In Ullrich, V., Hildebrandt, A., Roots, I., Eastabrook, R.W. (Eds.) Microsomes and Drug Oxidations (1976). Pergamon Press, Oxford, pp 16O-I69. 

BENZO(a)PYRENE HYDROXYLASE (AHH) ACTIVITY OF A RECONSTITUTED MIXED-FUNCTION OXIDASE SYSTEM CONTAINING HEPATIC CYTOCHROME P-448 FROM DBA-TREATED MALE SKATES... 

After removal of free Emulgen 913 from partially purified hepatic cytochrome P-448 of DBA-treated male skates an active mixed-function oxidase system was reconstituted by preincubating the cytochrome with purified rabbit hepatic NADPH-cytochrome o... 

Bend, J. R., Bogar, A., and Foureman, G. L. Partially induced hepatic microsomal mixed-function oxidase systems in individual winter flounder, Pseudoplenroneates ameriaanus, from coastal Maine. Bull. Mt. Desert Island Biol. Lab. (1977) 17 47-49. 

Philpot, R. M., Arinc, E. and Fouts, J. R. Reconstitution of the rabbit pulmonary mixed-function oxidase system from solubilized components. Drug Metab. Dispos. (1975) 3 118-126. 

Bend, J.R., Pohl, R.J. and Fouts, J.R. Further studies on the microsomal mixed-function oxidase system of the little skate, Raja erinacea, including its response to some xenobiotics. Bull. Mt. Desert Island Biol. Lab. (1973) 13 9-13. 

Considerable interest has developed concerning the nature of the mixed function oxidase system in fish and the role that this system may play in the development of toxic responses in these animals. Studies have shown that components of the mixed function oxidase system are present in relatively high concentrations in fish liver (4, 5, 6) and that the enzyme systems in this organ are capable of many of the biotransformation reactions already described for the mammalian liver (7, 8, 9). The presence of this complement of enzymes in the livers of many fishes suggests that this organ too may be particularly sensitive to insult from sub lethal concentrations of many waterborne toxicants. For this reason, methods to evaluate liver function in fish may be particularly useful in identifying the sublethal effects of certain classes of toxicants. 

Bergh AF, Strobel HW. 1992. Reconstitution ofthe brain mixed function oxidase system purification of NADPH-cytochrome P450 reductase and partial purification of cytochrome P450 from whole rat brain. J Neurochem 59 575-581. 

Boersma, D.C., Ellenton, J.A., and Yagminas, A. Investigation of the hepatic mixed-function oxidase system in herring gull embryos in relation to environmental contaminants. Environ. Toxicol. Chem., 5(3) 309-318,1986. 

The skin not only is a barrier to restrict diffusion of chemicals into the body, it is also an organ that can metabolize a variety of topically applied substances before they become systemically available. The skin has many of the same enzymes as the liver. The activities of several cutaneous enzymes in whole skin homogenates have been measured and compared to hepatic activity in the mouse. The activities of the enzymes in the whole skin homogenates were typically 2-6% of the hepatic values. However, there is evidence that the enzymes are present primarily in the epidermis. Because the epidermis makes up only 2-3% of the total skin, the real activities may range from 80% to 240% of those in the liver. Enzyme systems present include a qrtochrome P-450 system and a mixed-function oxidase system. 

The mechanism of carbon tetrachloride hepatotoxicity generally is viewed as an example of lethal cleavage, where the CCh— Cl bond is split in the mixed-function oxidase system of the hepatocytes. After this cleavage damage may occur directly from the free radicals (-CCl and -Cl) and/or from the formation of toxic metabolites such as phosgene." ... 

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). 

The plasma protein binding of tacrolimus is approximately 99%. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein and has a high level of association with erythrocytes. It is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P450 system (CYP3A). The disposition of tacrolimus from whole blood was biphasic with a terminal elimination half-life of 11.7 hours in liver transplant patients. 

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