Mixed-function oxidase system, microsomal

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 ... 

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. 

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. 

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. 

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. 

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). 

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. 

In addition to alcohol dehydrogenase, ethanol can be oxidized to acetaldehyde by the microsomal mixed-function oxidase system (cytochrome P450 2 El), as illustrated in Figure 35.1. Although this microsomal ethanol-oxidizing system probably has minor impor-... 

MICROSOMAL MIXED FUNCTION OXIDASE SYSTEM PHASE I REACTIONS... 

Microsomal Mixed Function Oxidase System Phase I Reactions... 

There are several known effects of BHA treatment which have been proposed to reduce the levels of reactive metabolites of BP which bind to DNA. It has been demonstrated that BHA feeding alters the microsomal mixed-function oxidase system in mice and rats (7,17-19). Several studies suggest that BHA treatment does not decrease the amounts of BP-7, 8-diol formed (7,20,21) whereas there is some indirect evidence that BHA treatment alters the metabolism of BP-7,8-diol (3,20) An induction by BHA of an lsozyme(s) of cytochrome P-450, which has kinetics of metabolism of BP-7,8-diol different than that of the constitutive isozyme(s), could account for the BHA-induced shifts in the dose-response curve for BPDEI-DNA adduct levels (15). 

Aryl hydrocarbon hydroxylase (AHH) is part of the microsomal mixed-function oxidase system involved in the detoxification of polycyclic aromatic hydrocarbons. In the HPLC assay developed for the AHH activity, benzo[a]pyrene (BaP) is used as the substrate, and the activity is determined by measuring the unreacted BaP during the reaction. 

Chloroethanes have been shown to undergo dechlorination by an enzyme system that is similar to the hepatic microsomal mixed function oxidase system (Van Dyke and Wineman 1971). Dechlorination was inducible by phenobarbital and required oxygen and NADPH. However, dechlorination also required a factor from the cytosolic fraction of the liver homogenate for optimal dechlorinating activity. In terms of structural requirements, dechlorination was enhanced if the carbon atom containing the chlorine had only one hydrogen. In a microsomal incubation, 13.5% of... 

Maloney AG, Schmucker DL, Vessey DS, Wang RK. The effects of aging on the hepatic microsomal mixed-function oxidase system of male and female monkeys. Hepatology 1986 6 282-7. 

The principal biotransformation of toxicants is catalyzed by the microsomal mixed function oxidase system (MFO). A deficiency of essential fatty acids generally depresses MFO activities. This is also true with protein deficiency. The decreased MFO has different effects on the toxicity of chemicals. For example, hexobarbital and aminopyrine are detoxified by these enzymes and are thus more toxic to rats and mice with these nutrient deficiencies. On the other hand, the toxicity of aflatoxin is lower in such animals because of their depressed bioactivation of this toxicant. MFO activities are decreased in animals fed high levels of sugar. 

OH-A -THC were incubatedin an in vitro rat liver microsomal NADPH-generating system ( ). Despite the low yield, the presence of the fatty acid-conjugated cannabinoids in the incubation mixture led our laboratory to assume that this commonly used microsomal mixed function oxidase system was involved in the conjugating process. Soon, however, it was confirmed that an energy-dependent... 

The CoA-fortlfled microsomal enzyme system was inhibited by SKF 525-A (B-diethylaminoethyl-diphenylpropyl acetate) and by 2,4-dlchloro-6-phenylphenoxyethylamine HBr (DPEA) in a dose-dependent fashion (28). Both are known inhibitors of the classical hepatic microsomal mixed-function oxidase system. This inhibition has been suggested to Involve a nonspecific binding to liver microsomal proteins and/or phospholipids (18.19). Binding to phospholipids would support the hypothesis proposed by Swell and co-workers (10) that fatty acyl CoA derivatives were not necessarily the only immediate source for the fatty acid moieties of the conjugates that phospholipids may act as the fatty acids reservoir in the CoA-fortified enzyme system. However, it is also known that cholesterol esterification is very sensitive to the fluidity of the microsomal membrane (12). The reduced conjugation produced when... 

Govindwar SP, Kachole MS, Pawar SS. 1988. Effect of caffeine on the hepatic microsomal mixed function oxidase system during phenobarbital and benzo[a]pyrene treatment in rats. Toxicol Lett 42(2) 109-115. 

Kato N, Tani T, Yoshida A. 1981b. Effect of dietary quality of protein on liver microsomal mixed function oxidase system, plasma cholesterol and urinary ascorbic acid in rats fed PCB. J Nutr 111 123-133. 

In the liver, oxidation reactions are catalysed by a group of enzymes known as the microsomal mixed function oxidase system or the cytochrome P450 enzyme family. Oxidative reactions take place in many other tissues as well. 

The polycyclic aromatic hydrocarbon carcinogens, which are very ubiquitous, are metabolized by the microsomal mixed-function oxidase system of target tissues to a variety of metabolites such as phenols, quinones, epoxides, dihydrodiols and dihydrodiol-epoxides ( ). The mqjor pathway of activation of benzo(a)pyrene (BP) leads to the formation of dihydrodiol-epoxide of BP which interacts predominantly with the 2-amino of guanine of DNA. The dihydrodiol-epoxide of BP appears to be the major ultimate electrophilic, mutagenic, and carcinogenic metabolite of BP ( ). Nevertheless, other metabolites such as certain phenols, epoxides and quinones may contribute to the overall carcinogenic activity of BP. In addition, a free radical mechanism may also be partly involved in its carcinogenic activity. 

Microsomal ethanol-oxidizing system (MEOS) At blood ethanol levels below 100 mg/dL, this liver microsomal mixed-function oxidase system contributes little to ethanol metabolism. However, the MEOS increases in activity with chronic exposure to ethanol or to inducing agents such as barbiturates, and this increase may be partially responsible for the development of tolerance. 

The microsomal mixed-function oxidase system containing multiple forms of cytochrome P-450 is the catalytic site for the initial oxidation of BaP. The primary products are the 2,3-, 4,5-, 7,8-, and 9,10-epoxide. The 4,5-epoxide has been isolated, while the formation of the other epoxides was demonstrated indirectly (757, 754, 236, 415, 428, 482, 505, 506). Primary oxidation at the 6 position results in formation of the unstable 6-hydroxy-BaP which is further oxidized by way of the 6-oxo radical to the 1,6-, 3,6-, and 6,12-quinones 290, 291, 350, 351). The major phenolic metabolite of BaP is 3-hydroxy-BaP lesser amounts of 1-, 7-, and 9-hydroxy-BaP are also formed. These phenols are produced at least partially by nonenzymatic rearrangement of the epoxides (the NIH shift 85, 93, 164, 236, 272, 416, 422, 424, 428, 482, 505, 506). 

The co-hydroxylation of fatty acids, which involves the addition of a hydroxyl group at or near the co-terminal carbon, was first shown to be catalyzed by the liver microsomal enzyme system in the 1960s [38], In particular, the CO pigment of CYP was recognized as a constituent of the microsomal mixed function oxidase system that contributes to the co-hydroxylation of steroids [39], Substrates that are susceptible to co-hydroxylation include laurate and AA [38], Early reports showed that CYP enzymes catalyze the CO (C-20) and co-1 (C-19) hydroxy lation of AA [40], In 1990, Faick et al. demonstrated that CYP enzymes also hydroxy late the C-16 (co-4), C-17 (co-3), and C-18 (co-2) carbons of A A [41], Thus, in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) and molecular oxygen, CYPs mediate the hydroxylation of AA to generate a variety of co-terminal HETEs including 16-, 17-, 18-, 19-, and 20-HETR (Fig. 13.2). 

AFBi and many of its metabolites require activation by the microsomal mixed function oxidase system into a mutagenic (Garner et al., 1972 Wong and Hsieh, 1976) or clastogenic (Stich and Laishes, 1975) species. The ultimate reactive molecule is believed to be AFB] -2,3-oxide (Lin et al., 1978 Neal and Colley, 1978). 

Eisele, T.A., Loveland, R.M., Kruk, D.L., Myers, T.R., Sinnhuber, R.O. and Nixon, 3.E. (1982). Effect of cyclopropenold fatty acids on the hepatic microsomal mixed function-oxidase system and aflatoxin metabolism In rabbits. Food Chem. Toxicol.. 20, 407-412. 

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