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Results for “Mixed Function Oxygenases”

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PubMed1978

Metabolism of cyclohexane carboxylic acid by Alcaligenes strain W1.

Thirty-three microorganisms capable of growth with cyclohexane carboxylate as the sole source of carbon were isolated from mud, water, and soil samples from the Aberystwyth area. Preliminary screening and whole-cell oxidation studies suggested that, with one exception, all of the strains metabolized the growth substrate by beta-oxidation of the coenzyme A ester. This single distinctive strain, able to oxidize rapidly trans-4-hydroxycyclohexane carboxylate, 4-ketocyclohexane carboxylate, p-hydroxybenzoate, and protocatechuate when grown with cyclohexane carboxylate, was classified as a strain of Alcaligenes and given the number W1. Enzymes capable of converting cyclohexane carboxylate to p-hydroxybenzoate were induced by growth with the alicyclic acid and included the first unambiguous specimen of a cyclohexane carboxylate hydroxylase. Because it is a very fragile protein, attempts to stabilize the cyclohexane carboxylate hydroxylase so that a purification procedure could be developed have consistently failed. In limited studies with crude cell extracts, we found that hydroxylation occurred at the 4 position, probably yielding the trans isomer of 4-hydroxycyclohexane carboxylate. Simultaneous measurement of oxygen consumption and reduced nicotinamide adenine dinucleotide oxidation, coupled with an assessment of reactant stoichiometry, showed the enzyme to be a mixed-function oxygenase. Mass spectral analysis enabled the conversion of cyclohexane carboxylate to p-hydroxybenzoate by cell extracts to be established unequivocally, and all of our data were consistent with the pathway: cyclohexane carboxylate --> trans-4-hydroxycyclohexane carboxylate --> 4-ketocyclohexane carboxylate --> p-hydroxybenzoate. The further metabolism of p-hydroxybenzoate proceeded by meta fission and by the oxidative branch of the 2-hydroxy-4-carboxymuconic semialde-hyde-cleaving pathway.

Alcaligenes↗

PubMed1979

Microsomal biphenyl 2-hydroxylation in the presence of some carcinogenic alkylaryltriazenes.

A hepatic mixed-function oxygenase system gave enhanced biphenyl 2-hydroxylation in the presence of known carcinogens in vitro and was therefore suggested as a convenient short-term assay for the detection of potentially dangerous compounds. However, the test did not yield the expected increase of biphenyl 2-hydroxylation with any of 8 selected carcinogenic triazenes. The new data are discussed in relation to the original supposition and to the hydroxylation pattern of various triazene substrates in vivo.

Animals↗

PubMed1983

6 beta-hydroxycortisol in random urine samples as an indicator of enzyme induction.

6 beta-Hydroxycortisol (6 beta-OHF) is a major cortisol metabolite formed primarily in the hepatic reticulum by mixed-function oxygenases. Changes in 6 beta-OHF may be used to detect enzyme induction by drugs or disease. Excretion of 6 beta-OHF must be corrected for change in urinary free cortisol (FF) excretion to allow for changes in cortisol production. We report the absence of circadian changes in 6 beta-OHF/FF ratios. Thus random measurements of 6 beta-OHF/FF ratios may be used to detect enzyme induction. This approach greatly simplifies noninvasive screening for enzyme induction.

Child↗

PubMed1990

Monoterpene biosynthesis: specificity of the hydroxylations of (-)-limonene by enzyme preparations from peppermint (Mentha piperita), spearmint (Mentha spicata), and perilla (Perilla frutescens) leaves.

Microsomal preparations from the epidermal oil glands of Mentha piperita, Mentha spicata, and Perilla frutescens leaves catalyze the NADPH- and O2-dependent allylic hydroxylation of the monoterpene olefin (-)-limonene at C-3, C-6, and C-7, respectively, to produce the corresponding alcohols, (-)-trans-isopiperitenol, (-)-trans-carveol, and (-)-perillyl alcohol. These transformations are the key steps in the biosynthesis of oxygenated monoterpenes in the respective species, and the responsible enzyme systems meet most of the established criteria for cytochrome P450-dependent mixed function oxygenases. The reactions catalyzed are completely regiospecific and, while exhibiting only a modest degree of enantioselectivity, are highly specific for limonene as substrate. Of numerous monoterpene olefins tested, including several positional isomers of limonene, only the 8,9-dihydro analog served as an alternate substrate for ring (C-3 and C-6) hydroxylation, but not side chain (C-7) hydroxylation. In addition to the regiospecificity of the allylic hydroxylation, these enzymes are also readily distinguishable based on differential inhibition by substituted imidazoles.

Cyclohexenes↗

PubMed1982

Hydrocarbon metabolism and cortisol balance in oil-exposed ringed seals, Phoca hispida.

1. Ringed seals were exposed experimentally to oil contamination, by feeding of a [14C]naphthalene marked crude oil in fish for up to 4 days at a rate of 5 ml/day. 2. Mixed function oxygenase (MFO) activity, measured as aryl hydrocarbon hydroxylase in liver and kidney, was found to be induced, in particular in kidney tissue where the activity increased 3-fold. 3. MFO induction correlated with a high degree of conversion of crude oil hydrocarbons to water-soluble metabolites. Most of the radioactivity was found in the polar fraction of plasma and urine. 4. Plasma cortisol levels were somewhat elevated by captive holding, and increased markedly after oil-exposure. Cortisol half-life decreased after oil exposure from 1 3/4 to 1 hr.

Animals↗

PubMed1981

[Lipid peroxidation and damage to the mixed function oxidase system in membranes of the endoplasmic reticulum in the presence of liver ischemia].

The content of endogenous lipid peroxidation products and variations in mixed function oxygenases were examined in liver microsomes of rats exposed to thermal ischemia of varying duration (15, 30, 60 and 120 min). The development of ischemic injury was accompanied by the accumulation of lipid hydroperoxides and Schiff's base, by the lowering of the content of cytochrome P-450 and diminution of the activity of NADPH-cytochrome P-450 reductase. The maximum changes were demonstrated 2 hours after ischemia. The presence of a reverse correlation between the content of lipid peroxidation products and the content of cytochrome P-450 was recorded.

Animals↗

PubMed1983

[Effect of phenobarbital on the cytogenetic activity of cyclophosphamide].

The effect of phenobarbital (PB, 2 and 80 mg/kg, 3 intraperitoneal injections) on the rate of chromosomal aberrations in the bone marrow cells of rats induced by a single intraperitoneal injection of cyclophosphamide (CP) in a dose of 25 mg/kg was studied. Activity of mixed function oxygenase (MFO) was evaluated from the content of cytochrome P450, b5 and activity of aniline hydroxylase. The rate of the cells with chromosomal aberrations in the bone marrow after combined action of PB and CP did not depend on the PB dose and was significantly higher as compared with CP action alone. After injection of 2 mg/kg, PB activity of MFO did not differ from that in control and increased 2 times after 80 mg/kg. Combined action of PB and CP did not induce any significant changes in activity of MFO compared with PB alone.

Animals↗

PubMed1981

Assessing consequences of marine pollution by hydrocarbons using sponges as model organisms.

Pollution has been assessed as a mutagenic activity determined by the Ames test, using radiolabelled benzo[a]pyrene (BaP) as a model pollutant. Experimental animals were sponges, mainly Tethya lyncurium from the Northern Adriatic and from the Pacific near Catalina Island, California, U.S.A. Changes in ornithine decarboxylase (ODC) activity (ODC; EC 4.1.1.17) and polyamine concentrations with and without pollution were observed. There is a slow rise in ODC activity during the course of three-weeks exposure and a fast increase of polyamine levels during the course of one day. Mixed function oxygenase (MFO; EC 1.14) activity could not be detected in sponges. There was a significant concentration dependent coupling of radioactive BaP derivatives (BaPD) to the macromolecular fractions; the highest in protein, X 1000 greater than DNA and X 500 greater than RNA. Coupling is light-mediated and drops to zero in the dark. However when activated microsomal fractions from fish, that had been exposed to high level polycyclic aromatic hydrocarbon (PAH) pollution are added, dark incorporation rises to significant levels which can be decreased by the MFO inhibitor 7,8-benzoflavone (BP). The question of possible absence of DNA repair in the sponges and some implications are discussed.

Animals↗

PubMed1982

The effect of benzo[a]pyrene on sponges as model organisms in marine pollution.

The majority of the investigations were performed with the marine sponge Tethya lyncurium at concentrations of 2 X 10(-8) to 1 X 10(-11) g/ml of benzo[a]pyrene (BaP). Sea-pollution was characterized as BaP equivalent activity in the Ames test. Increased activity of ornithine decarboxylase (ODC) was observed when sponges were artificially exposed at polluted marine areas for 3 weeks. In contrast to the situation in higher animals no ODC induction of the fast type was observed. Mixed function oxygenases (MFO) were not detected in sponges nor could they be induced as in vertebrates. BaP was absorbed by Tethya and concentrated 30--60-fold. In live, but not dead, artificially perfused sponges [3H]- and [14C]BaP-radiolabeled became firmly associated with DNA, RNA and protein of the sponges. The association persisted in isolated fractions, in nucleotides, in nucleosides and in protein hydrolysates. The BaP binding ratio to DNA was found to be strongly correlated to the concentration of BaP. Light modifies BaP and thus enables binding. In the dark only very low association, if any, is observed. The possible consequences of these findings are discussed.

Animals↗

PubMed1983

Carcinogenic effects of intracolonic benzo[a]pyrene in beta-naphthoflavone-induced mice.

Benzo[a]pyrene (BP) was administered intracolonically to ICR/Ha and C57Bl/6 female mice, 1 mg/mouse, once weekly for 14 weeks. Half of the mice received beta-naphthoflavone (beta-NF, a mixed-function oxygenase inducer) i.p. 24 h prior to the BP. No colonic neoplasms were found in any of the mice after 18 months. However, the BP treatment did cause a significant increase in numbers of primary lung tumors, forestomach papillomas, mammary carcinomas, and sarcomas in one or both strains, relative to controls, and the incidence of all of these except for the sarcomas was significantly reduced by treatment with beta-NF prior to BP. Overall, the beta-NF pretreatment reduced total incidence of neoplasms by about 30% in the ICR/Ha mice and by about 60% in the C57Bl/6 mice, and did not potentiate the action of the carcinogen in any organ.

Animals↗

PubMed1989

Interactions of heterocyclic Maillard products with the hepatic microsomal monooxygenase system.

1. Interactions of methyl-substituted pyrazines, and other constituents of Maillard products generated during heat treatment of food, with hepatic microsomal mixed-function oxygenases were studied in vitro. 2. Spectral interactions of N-containing heteroaromatic compounds with the cytochrome P-450 system are type I or type II depending on the state of induction, and are relatively weak. Inhibition of 7-ethoxycoumarin O-deethylation by these compounds is ten times lower than that of metyrapone, agreeing with the weak spectral interaction. Inhibition is competitive for 2,3-dimethylquinoxaline, and complex for 2,5-dimethylpyrazine and 2,3,5,6-tetramethylpyrazine. 3. Spectral and inhibitory interactions indicate biotransformation. This was studied with 2,3,5,6-tetramethylpyrazine; the metabolite formed was identified as 2-hydroxymethyl-3,5,6-trimethylpyrazine. Metabolism to the N-oxide did not occur.

7-Alkoxycoumarin O-Dealkylase↗

PubMed1975

Effect of dietary substitution of sucrose and its constituent monosaccharides on the activity of aromatic hydroxylase and the level of cytochrome P-450 in hepatic microsomes of growing rats.

The effect of dietary substitution of starch by sucrose, glucose, fructose or an equimolar mixture of glucose and fructose on the activity of biphenyl hydroxylase and the level of the major terminal mixed function oxygenase, cytochrome P-450, has been studied in hepatic microsomal preparations from growing rats. The substitution of sucrose for starch depressed the contration and total activity per liver of biphenyl 4-hydroxylase and the concentration, but not the total amount, of cytochrome P-450 in weanling rats. The absolute amount of these enzymes in whole liver was not, however, similarly depressed by the constituents of sucrose, namely glucose and fructose, either when given alone or in equimolar mixture. All these sugars, however, depressed the total activity of biphenyl 2-hydroxylase. The activity of biphenyl 4-hydroxylase in the liver of weanling rats, but not of adults, was reduced when the level of sucrose in the diet was reduced from 60 to 10%.

Animals↗

PubMed2006

Effects of methyl parathion on Chasmagnathus granulatus hepatopancreas: protective role of sesamol.

The protective role of sesamol, an inhibitor of the mixed function oxygenase (MFO) system, against histopathological effects of methyl parathion in the hepatopancreas of the estuarine crab, Chasmagnathus granulatus, was studied. Exposure (72 h) to a sublethal dose (0.05 mg/kg/day; 10% of 72 h-LD50) of injected methyl parathion increased the percentage of damaged hepatopancreatic tubules. Presence of melanin-like deposits in the connective tissue between hepatopancreatic tubules was also observed. Antioxidant enzyme activities (catalase and glutathione S-transferase) and lipid peroxidation (LPO) levels were also increased in hepatopancreas of crabs injected with methyl parathion. Pretreatment with sesamol (0.85 mg/kg/day) significantly protected against all these effects. These findings suggest that the hepatopancreatic damages induced by methyl parathion are due to LPO of hepatopancreatocytes membranes, as a consequence of the oxidative stress generated after methyl parathion oxidative biotransformation mediated by the MFO system.

Animals↗

PubMed1997

A multidisciplinary approach using several biomarkers, including a parasite, as indicators of pollution: a case history from a paper mill in Newfoundland.

Several biomarkers are currently used to determine chronic exposure of fish to environmental contaminants. In studies to assess the effects of pulp mill effluent on winter flounder (Pleuronectes americanus), body and hepatosomatic indices (HSIs), histopathology, levels of hepatic detoxifying enzymes, mixed function oxygenases (MFO), muscle acetylcholinesterase (Ache) and selected parasite abundance were compared in samples taken near a paper mill (sulphite-bleaching) and a number of reference sites. Our studies revealed a number of significant (P < 0.05) differences between samples taken near the paper mill and reference sites. Flounder captured at two locations near the mill were greater in length and weight, had elevated HSIs and more lesions in the liver and spleen while an acanthocephalan, Echinorhynchus gadi, located in the digestive tract, was lower than at more distant sites. Activity of MFO and Ache were similar at most sites and might be a reflection of the fish's foraging behaviour and consequently intermingling of populations from different locations during summer. These results support the view that several biomarkers should be utilised when assessing the health of fish living in habitats degraded by pollutants.

Acanthocephala↗

PubMed1989

Enzymatic detoxification using lipophilic hollow-fiber membranes: III. Oxidation reactions of sulfides.

A lipophilic hollow-fiber membrane preparation that was previously described for glucuronidation and sulfation reactions was used for the enzymatic oxidation of sulfides. Endogenous and exogenous toxins in buffer solution or in serum or blood of intoxicated animals were circulated through the internal lumen of lipophilic hollow fibers. Native liver microsomes of the rabbit were circulated on the outside of the hollow fibers. Lipophilic toxins accumulate in and penetrate through the lipophilic membrane and the toxins are oxidized by the mixed function oxygenase system of liver microsomes. The oxidized products cannot rediffuse to the donor side. The endogenous toxin dimethylsulfide (DMS) was converted on the enzyme side to dimethylsulfoxide (DMSO) and small amounts of dimethylsulfone, which are hydrophilic and nontoxic substances. Other sulfide compounds, ethylmethylsulfide (EMS) and s-butylmethylsulfide (BMS), have also been converted to their oxidized forms. The enzymatic clearance of the hollow-fiber module for DMS in in vivo experiments in the rabbit was found to be 1.30 nmol/h/mg protein/cm2 hollow-fiber surface. The transmembranous enzymatic clearance of the in vitro oxidation reactions of DMS, EMS, and BMS in buffer solutions (open circuit) were measured, respectively, as 1.63, 3.45, and 5.16 nmol/h/mg protein/cm2 hollow-fiber surface. This technique allows the enzymatic oxidation of sulfur compounds with liver microsomes in vitro and in vivo without immunological hazards, and it is suited for artificial liver support.

Animals↗

PubMed1992

Milt characteristics, reproductive performance, and larval survival and development of white sucker exposed to bleached kraft mill effluent.

White sucker from a Lake Superior bay which receives bleached kraft mill effluent (BKME) show increased hepatic mixed-function oxygenase (MFO) activity, reduced plasma sex steroid levels, decreased egg and gonad size, a decrease in the occurrence of secondary sexual characteristics, and an increased age to maturation. This study evaluated the reproductive performance of that white sucker population relative to a similar reference population. Spawning male white sucker from the BKME site had reduced spermatozoan motility but no significant differences in milt volume, spermatocrit levels, or seminal plasma constituents. BKME male and female fish had equal or greater fertilization potential compared to both male and female fish at the reference site. There was no difference either in the hatchability of the eggs or in larval size at hatch. BKME larvae did show reduced growth rates by 24 days posthatch but showed equal rates of yolk utilization. No difference in larval MFO activity was detected between sites at 21 days posthatch, indicating no parental transfer of induction to the progeny.

Animals↗

PubMed1996

Involvement of cytochrome b5 in the metabolism of tetrachlorobiphenyls catalyzed by CYP2B1 and CYP1A1.

The role of cytochrome b5 in the cytochrome P450 (CYP)-dependent hydroxylation of tetrachlorobiphenyl (TCB) isomers was examined using a reconstituted mixed function oxygenase (MFO) system containing purified CYP2B1 or 1A1, and rat liver microsomes. Hydroxylations of 2,2',5,5'- and 3,3',4,4'-TCBs were catalyzed mainly by CYP2B1 and 1A1, respectively, in the reconstituted MFO system and those of 2,3',4',5- and 2,3',4,4'-TCBs were mediated by both cytochrome P450 systems. The activity toward 2,2',5,5'- and 2,3',4',5-TCB was significantly increased 6.5- and 5.5-fold, respectively, by addition of cytochrome b5 in the reconstituted MFO system containing of CYP2B1. Either hydroxylation activity toward 2,3',4,4'-TCB with the CYP2B1 system was very low or decreased by addition of cytochrome b5. These results suggest that the involvement of cytochrome b5 to the hydroxylation of TCBs is dependent on the TCB congener being metabolized, and the cytochrome P450 isoform involved in its metabolism.

Animals↗

PubMed1980

Different tissue responses of mixed function oxidases and detoxifying enzymes to aflatoxin B1 administration in the rat.

The carcinogenic effects of aflatoxin B1 have been related to the formation of an active intermediate metabolite, an epoxide produced via the cytochrome P-450-mediated mixed function oxidase. The toxicity of this intermediate is dependent on metabolic transformations by enzymes such as aryl hydrocarbon hydroxylase, glutathione S-transferase and glutathione peroxidase. Like the mixed function oxygenase, these enzymes are inducible, and dependent on the action of specific drugs and inducers. The present study describes the effect of a single sublethal i.p. dose (6 mg/kg body wt) of aflatoxin B1 on the specific activities of microsomal demethylases, aryl hydrocarbon hydroxylase (AHH), glutathione S-transferase and glutathione peroxidase in rat liver, kidney, lung, brain and adrenals. The enzymes were assayed 24 h after the toxin treatment. Among the different tissues, only liver AHH showed an induction on toxin treatment whereas those of kidney and brain declined. Microsomal demethylase was also high in liver and low in kidney. However, no significant alteration was induced by aflatoxin B1 on glutathione S-transferase and glutathione peroxidase activities in the various tissues examined except the adrenals, which showed a significant increase. The present study revealed that the reaction sequence for metabolic transformation of aflatoxin B1 is more complex than foreseen from the activities of these inducible metabolite-transforming enzymes.

Aflatoxins↗