Mixed function oxidase system microsomal metabolism

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. 

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... 

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). 

The characteristics of this reaction were studied by Burstein and Kupfer (7) who showed that it followed the pattern of a typical mixed-function oxidase system. They showed that all the metabolizing activity occurred in the microsomal fraction and that oxygen and NADPH were required. Other agents such as SKF-525A (8-di-ethylaminoethyldiphenylpropyl acetate), Burstein and Kupfer (8), and DDT, Kupfer et al. (9), were reported to inhibit this hydroxylation process. 

Further biotransformations of A" VPA involve both the liver microsomal CYP enzymes and the fatty acid (3-oxidation pathway (Figure 33.29). The mixed-function-oxidase system metabolizes the unsaturated metabolite to a -butyrolactone derivative through a chemically reactive entity that is a mechanism-based inhibitor of CYP. The alkylation of the prosthetic heme by means of the radical occurs prior to formation of the epoxide. Thus, the epoxide is not involved in the CYP inhibition. 

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. 

Erythromycin diffuses readily into most tissues except the brain and cerebrospinal fluid. Erythromycin crosses the placental barrier and is present in maternal milk [18]. In many animal species and humans, erythromycin is metabolized by the hepatic microsomal cytochrome P-450 mixed function oxidase system. More specifically erythromycin appears to act as a substrate for the cytochrome P-450 3A4 (CYP 3A4) isoform [13]. Erythromycin is excreted primarily in the bile only 2-5% is excreted in the urine. Concentrations in the bile may exceed 10 times those in plasma [19]. 

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 confusion on the mechanism of the comutagenesis and mutagenesis of these pyrolysis products, especially pertaining to the enhancement and inhibition effects of Harman and Norharman,centers around the problem of the lack of certain fixed variables in the experimentation, particularly, the availability of the purified enzymes involved in the metabolic activation, which constitute the cytochrome P-450 mixed function oxidase system. We, therefore, undertake this problem to elucidate the mechanism of microsomal metabolism of these oyrolysis products with the purified mixed function oxidase(MFO) system. 

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. 

The biotransformation systems involved in insecticide metabolism have been studied in the R and S populations to determine any differences which might be potential contributory factors to or results of insecticide resistance. In addition, the possibility of mixed-function oxidase induction has been investigated. Specifically, the studies have encompassed a seasonal study of microsomal mixed-function oxidase (mfo) components, and studies of aldrin, dieldrin and DDT metabolism. 

Vinylidene fluoride is taken up rapidly via the pulmonary route in rats, but at equilibrium the mean concentration (by volume) in rats was only 23% of that in the gaseous phase. Metabolism proceeded very slowly and was saturable at exposure concentrations of about 260 mg/m Its maximum rate was 1% that of vinyl chloride and less than 20% that of vinyl fluoride there has been a report of an increase in the urinary excretion of fluoride in exposed rats. No alkylating intermediate was demonstrated after passage through a mouse-liver microsomal system. However, vinylidene fluoride inhibits mixed-function oxidase activity in vitro and, like similar halogenated compounds that are transformed to reactive metabolites, it alters rat intermediary metabolism, leading to acetone exhalation (lARC, 1986). 

Many pyrrolizidine alkaloids are metabolized to toxic pyrrole metabolites in the liver by mixed-function oxidases. The structural and chemical features necessary for the formation of these metabolites have been discussed.77 The most important features, in addition to the 3-hydroxymethyl-3-pyrroline system, are steric hindrance to hydrolysis of the ester, lipophilic character (favouring attack by the hepatic microsomal enzymes), and the presence of a conformation that allows preferential oxidation of the pyrroline ring rather than 7V-oxidation. The alkylating activities of a series of these pyrrole derivatives have been examined.78... 

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