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Results for “Mixed Function Oxygenases”

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PubMedDate not supplied

Effect of metronidazole on the hepatic mixed function oxygenases (cytochromes b5 and P-450) in Swiss mice.

Effect of metronidazole (MNZ) treatment (oral and ip) on activities of cytochrome b5 and P-450 was studied in male, virgin and pregnant female mice. Activities of both the cytochromes increased in virgin mice treated with 2 mg (ip or PO, per mouse) but not in male and pregnant females. 30 mg dose (per mouse) was toxic in pregnant mice but increased the cytochromes activities in males and virgin females. HPLC analysis of liver MNZ levels showed that virgin females had higher MNZ content than male and pregnant females when treated with ip injection of MNZ (250 mg/kg).

Animals↗
PubMed1987

Interrelationship between aminopyrine oxidation and gluconeogenesis in hepatocytes prepared from fructose-pretreated mice.

Aminopyrine oxidation was studied in isolated hepatocytes prepared from 24-h-starved mice (i) after induction of the NADPH-generating malic enzyme and glucose-6-phosphate dehydrogenase, but not the mixed function oxygenases by fructose, (ii) after induction of both mixed function oxygenases and NADPH-generating malic enzyme and glucose-6-phosphate dehydrogenase by phenobarbital and (iii) without any pretreatment. Phenobarbital pretreatment, as expected, increased the rate of aminopyrine oxidation of isolated hepatocytes. However, fructose pretreatment also enhanced the rate of N-demethylation of aminopyrine by more than 100% supporting the view that the availability of NADPH is rate limiting in drug oxidation under certain conditions. The role of malic enzyme and glucose-6-phosphate dehydrogenase in the NADPH supply for aminopyrine oxidation was investigated by the addition of two groups of gluconeogenic precursors: lactate or alanine and glycerol or fructose with the simultaneous measurement of glucose synthesis and aminopyrine N-demethylation. There was a clear correlation between the increased rate of aminopyrine oxidation and the decreases of glucose production caused by aminopyrine. Gluconeogenesis in the presence of 1 mM aminopyrine was decreased by 70-80% when alanine or lactate were used as precursors, it was decreased by only 35-40% when glucose production was started from glycerol or fructose; in an accordance with the facts that NADPH generation and gluconeogenesis starting from alanine or lactate share two common intermediates--malate and glucose-6 phosphate--, while there is only one common intermediate--glucose-6 phosphate--if fructose or glycerol are used. Similar results were obtained with the addition of the structurally dissimilar hexobarbital. It is concluded that besides malic enzyme, glucose-6-phosphate dehydrogenase also takes part in NADPH supply for drug oxidation in glycogen-depleted hepatocytes.

Aminopyrine↗
PubMed1985

Comparative metabolism and toxicity of chemical carcinogens in primary cultures of hepatocytes.

Hepatocytes were prepared by an in situ or biopsy perfusion of liver with collagenase. Hepatocytes from adult liver were cultured without serum on collagen-coated dishes in culture medium supplemented with hormones. Stable monolayers were established within 24 h and were maintained for up to 10 d. The hormone supplement maintained cytochrome P-450, a critical component of mixed function oxygenase responsible for activation of many procarcinogens. The addition of serum and phenobarbital to the cultures also maintained higher levels of mixed function oxygenase activity. Viable cultures were prepared from mice, rats, guinea pigs, rabbits, dogs, monkeys, and humans. Metabolism studies revealed the rate of metabolism and the extent of covalent binding to macromolecules, including DNA. Measures of cytotoxicity and genotoxicity in vitro provide an indication of hepatonecrotic and hepatocarcinogenic potency in vivo. Comparative metabolism, cytotoxicity, and genotoxicity studies provide a means of facilitating the extrapolation of toxicity data from laboratory animals to humans.

2-Acetylaminofluorene↗
PubMedDate not supplied

A decade of research on the environmental impacts of pulp and paper mill effluents in Canada: development and application of fish bioassays.

Laboratory tests have been used to assess the regulatory and research questions related to the effects of pulp mill effluents on aquatic biota. Acute, short-term laboratory tests have clearly shown the improvement in final effluent quality following installation of secondary treatment at Canadian pulp mills. In an effort to predict and investigate impacts on wild fish, laboratory bioassays were developed to examine sublethal endpoints: induction of hepatic mixed function oxygenase activity and reduction of sex steroid concentrations. These laboratory assays have been used to assess whole effluents, specific chemicals, and components of pulp mill processes, and to discriminate between historical and present-day effluent discharges. These tests have shown that induction of mixed-function oxygenase activity and reduction of sex steroid concentrations are produced by effluents from a variety of mill types, with and without chlorine bleaching, in hardwood and softwood pulping facilities, and before and after effluent treatment. These short-term bioassays have enabled reductions in sex steroid concentrations to be linked to mill process streams, and have provided information on effective waste stream treatment. Longer term, life-cycle fish bioassays have shown that chronic exposure to pulp mill effluents commonly results in growth enhancement, liver enlargement, and decreases in gonad size, secondary sex characteristics, and fecundity. These long-term laboratory exposures are able to mimic the most commonly observed alterations of wild fish exposed to pulp mill effluents: increases in condition factors, increases in liver-somatic indices, and decreases in gonadosomatic indices. This pattern of response is a combination of nutrient enrichment with metabolic disruption. The most sensitive and biologically meaningful endpoint is decreased reproduction in fish life-cycle exposures. As the laboratory tests move forward into the next decade, attention will focus on the reproductive endpoints and on the possibility of shortening the fish bioassays while still maintaining sensitivity and biological relevance.

Animals↗
PubMed1997

Differential effect of carbamazepine and valproate monotherapy on plasma levels of oestrone sulphate and dehydroepiandrosterone sulphate in male epileptic patients.

Steroid sulphates such as oestrone sulphate (OE1S) and dehydroepiandrosterone sulphate (DHEAS) have been suggested to be of biological importance in different disease states such as breast cancer and atherosclerosis. Previous studies have shown that drugs such as aminoglutethimide and rifampicin that induce P450-dependent mixed-function oxygenases selectively suppress plasma OE1S levels. The aim of this study was to evaluate the influence of treatment with carbamazepine, an antiepileptic drug known to stimulate mixed-function oxygenases, on plasma levels of OE1S and DHEAS. We measured plasma OE1S and DHEAS together with other plasma oestrogens and androgens in male epileptic patients before and during carbamazepine monotherapy. Patients treated with valproate monotherapy acted as a control group. Treatment with carbamazepine decreased plasma OE1S levels from a mean value of 810.8 to 411.6 pmol/l (mean suppression to 50.7% of pretreatment levels, P < 0.001). Similarly, the ratio of OE1S to OE1 fell to 59.9% of pretreatment levels (P < 0.001)). DHEAS decreased from a mean level of 4.9 mumol/l before treatment to 3.0 mumol/l during carbamazepine therapy (mean reduction to 62.7% of pretreatment levels (P < 0.001), while the ratio of DHEAS to DHEA fell to 63.0% of pretreatment values (P < 0.01). No significant change in plasma levels of the other oestrogens or androgens measured was observed. Treatment with valproate caused a slight decrease in FSH levels (P < 0.05), but no change in any of the other hormones measured was observed. Studies are warranted to evaluate the possible effects of long-term treatment with carbamazepine on the risk of developing endocrine-sensitive tumours and cardiovascular disease and also the possible effects of alterations in plasma DHEAS on epileptic activity.

Adolescent↗
PubMed1983

Investigation of adrenergic and prostaglandin influences in the endotoxin alteration of hepatic heme oxygenase, microsomal mixed-function oxidase, and glucocorticoid-induced tryptophan oxygenase activities.

The possible role for adrenergic influences or prostaglandins in the effects of endotoxin to inhibit the glucocorticoid induction of hepatic tryptophan oxygenase (TO) activity, to decrease the hepatic microsomal cytochrome P--450-dependent drug-metabolizing activity, and to induce heme oxygenase activity was examined. Administration of the alpha-adrenergic locking agents phenoxybenzamine or phentolamine attenuated the inhibitory effect of the bacterial lipopolysaccharide on the induction of TO activity by dexamethasone. Injection of a beta-adrenergic blocker, propranolol, or of indomethacin, an inhibitor of prostaglandin biosynthesis, accentuated the effect of endotoxin to inhibit TO induction. Neither phenoxybenzamine, propranolol, nor indomethacin altered the effect of endotoxin to decrease aniline hydroxylase activity, ethylmorphine N-demethylase activity, or the levels of cytochrome P--450. Also, dexamethasone administration did not significantly protect against the effects of endotoxin on the hepatic microsomal drug metabolizing enzyme system, and none of the pharmacological agents diminished the effects of endotoxin to induce hepatic heme oxygenase activity. Endotoxin administration was also shown to diminish, but not prevent, the induction of cytochrome P--450 and ethylmorphine N-demethylase activity produced by phenobarbital. The results indicate that alpha-adrenergic mechanisms are involved in the endotoxic inhibition of the glucocorticoid induction of TO activity and suggest that neither adrenergic influences nor prostaglandins play a significant role in the effect of endotoxin to decrease hepatic mixed-function oxidase activity.

Adrenergic alpha-Antagonists↗
PubMed1979

Studies on metabolic activation of vinyl chloride in Drosophila melanogaster after pretreatment with phenobarbital and polychlorinated biphenyls.

It is known that vinyl chloride is metabolized by the mixed function oxygenase system in the liver to reactive mutagenic and carcinogenic metabolites. This metabolic activation was studied in Drosophila melanogaster by measuring the uptake of 14C from labelled vinyl chloride in different strains and with different pretreatments with phenobarbital and polychlorinated biphenyl (PCB) Clophen A50), well known inducers of cytochrome P-450. In accordance with previously obtained data on vinyl chloride induced sex linked recessive lethals, it was shown that pretreatment with inducers increased the uptake of labelled compound up to ten times. There was, however, a marked difference in response between the five strains used. In particular, the strain Hikone, known to be resistant to insecticides, had a comparatively high initial radioactivity from vinyl chloride without any pretreatment, but it was not or insignificantly inducible with phenobarbital or PCB. Crosses between Hikone and an inducible strain indicated essentially a dominance for the Hikone genotype. Tests on inducible strains showed the same response to phenobarbital by 2 h old larvae and adult male and females. Dimethylsulphoxide (DMSO) used as a solvent decreased both the initial uptake of 14C and particularly the induction by PCB. The use of Tween 80 as an emulsifier did not have such an effect. It is emphasized that the interstrain variation in metabolic activation and inducability has to be taken into consideration in order to optimize the use of Drosophila for mutagenicity testing. This variation also opens up new possibilities of analyzing the mixed function oxygenase system biochemically and genetically.

Animals↗
PubMed2002

Bioavailability to juvenile rainbow trout (Oncorynchus mykiss) of retene and other mixed-function oxygenase-active compounds from sediments.

Retene (7-isopropyl-1-methylphenanthrene) is a naturally formed polycyclic aromatic hydrocarbon (PAH) that causes teratogenicity in fish larvae and induction of cytochrome P450 (CYP1A) enzymes. Retene occurs at high concentrations (< or =3,300 microg/g dry wt) in surface sediments contaminated by resin acids from pulp mill effluents. To assess the environmental risks of retene, it is important to evaluate conditions affecting its bioavailability and accumulation by fish. Fingerling rainbow trout were exposed to retene-spiked or naturally contaminated sediments and sampled after 4 d to determine liver CYP1A activity and concentrations of retene metabolites in bile as indicators of retene accumulation. Industrially contaminated sediments collected near a bleached kraft pulp and paper mill discharging to Lake Saimaa, Finland, significantly induced trout liver CYP1A activity, indicating accumulation of arylhydrocarbon receptor (AhR)-active ligands. Bile of these fish contained retene metabolites, providing direct evidence that retene is bioavailable, presumably via desorption from sediments. Induction of CYP1A in fish exposed to sediments spiked with retene or benzo[k]fluoranthene supported this conclusion. While the extent of CYP1A induction by spiked sediments declined after storage (i.e., aging), a portion of the spiked PAHs remained bioavailable. However, retene was not the sole CYP1A inducer in industrially contaminated sediments, as shown by induction in fish injected with sediment extracts oxidized to remove labile PAHs but not persistent organochlorine compounds such as chlorinated dioxins and furans.

Animals↗
PubMed1978

Variable inhibition of human hepatic drug metabolizing enzymes by disulfiram.

In healthy adult males, oral treatment with disulfiram exerted variable inhibitory effects on various metabolic parameters of the hepatic microsomal enzyme system: Two 10 mg/kg doses, given at an interval of 24 hr produced only a marginally significant prolongation of the plasma elimination half-life of antipyrine. This effect was not detectable when using as a criterion the formation of 4-OH-antipyrine (aromatic C-hydroxylation), as measured by its renal excretion. In contrast, a single dose of disulfiram (10 mg/kg) was followed by a significant decrease in the formation of D-glucaric acid, which was demonstrable for 6 days and was measured by the renal excretion of D-glucaric acid over 24-hr periods. The same single dose of disulfiram (10 mg/kg) did not affect the activity of the serum gamma-glutamyl transpeptidase. However, a single dose as small as 5 mg/kg caused a temporary but significant reduction in the formation of 4-aminoantipyrine from aminophenazone (oxidative demethylation), where the renal excretion of 4-aminoantipyrine provided a measure of the decrease. During the subsequent phase of excretion, the deficit in 4-aminoantipyrine elimination was completely compensated for. It is concluded from the results that in man the impairment of oxidative N-demethylation constitutes the most sensitive criterion of a measurable inhibitory effect of disulfiram on the hepatic mixed-function oxygenase system.

Adult↗
PubMed1981

Microsomal injury in the liver of rats treated with carbon tetrachloride.

The oral administration of CCl4 (2.5 ml/kg) to male rats inducted increase in the activity of serum GPT, accumulation of hepatic triglyceride, acceleration of depression in the activities of microsomal enzymes, disaggregation of hepatic polyribosomes, and decrease in the ability of in vitro protein synthesis 0.5 hr after the intubation. When, however, a small dose of CCl4 (0.25 ml/kg) were given, the defects in hepatic polyribosomes and mixed-function oxygenase system were most marked among the above toxic changes.

Alanine Transaminase↗
PubMed1984

Benzo[a]pyrene metabolism in marine fish and some analytical aspects of its metabolites.

In interspecies comparisons of benzo[a]pyrene metabolism, standardized procedures in the analysis of the metabolites must be established. Technical problems arising in metabolite analysis are discussed, and data are presented showing the activities of the mixed function oxygenase and transferase systems in phenobarbital- and 3-methylcholanthrene-induced mullet and killifish.

Animals↗
PubMed1979

Demonstration of drug-ethanol interactions by changes in activity of hepatic microsomal oxidase/oxygenase cytochrome P-450 function.

"Uncoupling" of microsomal hepatic oxygenases is characterized by a situation in which microsomal monooxygenases exhibit more oxidase than oxygenase activity with an increased formation of hydrogen peroxide at the expense of O2, NADPH and substrate hydroxylation. The importance of such in vitro observations with respect to physiological conditions "in vivo" has been tested by investigating elimination kinetics of ethanol. If hexobarbital, a substrate of mixed function oxygenase as well as an "uncoupler", is given to guinea pigs together with ethanol, changes in the elimination of ethanol occur. It is suggested that this is the consequence of an increased formation of H2O2 which contributes via peroxidatic reaction of catalase to the elimination of ethanol. The results also show additional interactions of hexobarbital as well as of ethylmorphine with ethanol elimination. Both compounds increased the initial blood levels of ethanol which precede accelerated elimination, probably by a first pass effect. At low concentrations of ethanol, ethylmorphine inhibits ethanol elimination by inhibition of ADH.

Alcohol Oxidoreductases↗
PubMed1987

Metabolism of monoterpenes: demonstration of the hydroxylation of (+)-sabinene to (+)-cis-sabinol by an enzyme preparation from sage (Salvia officinalis) leaves.

A microsomal preparation from the epidermis of Salvia officinalis leaves catalyzed the NADPH- and O2-dependent hydroxylation of the monoterpene olefin (+)-sabinene to (+)-cis-sabinol. The reaction catalyzed is a key step in the biosynthesis of C3-oxygenated thujane monoterpenes, and the hydroxylase is highly specific for (+)-sabinene as substrate. The hydroxylase from leaf homogenates was solubilized and characterized with regard to reaction conditions, inhibitors, and activators. Activity was partially inhibited by rabbit anti-rat cytochrome P-450 and by CO, and the latter inhibition was reversed by 450 nm light. A CO-difference spectrum and type I substrate binding spectrum were obtained. The hydroxylase meets most of the established criteria for a cytochrome P-450-dependent mixed function oxygenase and represents one of very few enzyme systems of this type to be isolated from leaves of a higher plant.

Bicyclic Monoterpenes↗
PubMed1990

BCNU-induced quantitative and qualitative changes in hepatic cytochrome P-450 can be correlated with cholestasis.

Male Sprague-Dawley rats were given single i.p. injections of 1,3-bis(2-chloroethyl)-1-Nitrosourea (BCNU) to investigate changes in hepatic microsomal cytochrome P-450 content and metabolic activity. On day 14 after treatment (20 mg/kg), cytochrome P-450 content had decreased by approximately 25% and ethylmorphine N-demethylase activity (nmol product/nmol P-450/min) had decreased by 36%. In contrast, ethylmorphine O-deethylase and 7-ethoxycoumarin O-deethylase activities were not significantly decreased by BCNU treatment. Hepatic delta-aminolevulinic acid synthetase activity was only 60% of control values, and microsomal heme oxygenase activity was slightly but not statistically elevated. Cytochrome P-450 content in control and BCNU-treated rats increased in a similar manner after phenobarbital or beta-naphthoflavone induction. Electrophoretic analysis of cytochrome P-450 proteins isolated from hepatic endoplasmic reticular membranes of treated and control rats suggested that alterations in these proteins occurred in BCNU-treated rats. These changes in cytochrome P-450 content and activity are very similar to those reported in isolated systems exposed to bile acids or in rats with experimentally produced cholestasis. BCNU has been shown to produce cholestasis, which precedes its effects on microsomal mixed-function oxygenase activity. Thus, the delayed effects of BCNU on microsomal drug metabolism are probably secondary to its interference with bile formation.

Animals↗
PubMed1979

Correlation of mixed-function oxidase activity with ultrastructural changes in the liver of a marine fish.

Specimens of mullet (Mugil cephalus), a marine fish, were given single doses of 3-methylcholanthrene intraperitoneally and the activity of the microsomal mixed-function oxygenase system in the liver was measured by the metabolism of benzo(a)pyrene. The enzyme system was found to be inducible with concomitant ultrastructural changes in the hepatocytes. The specific activity and the metabolic profile approximate those of the rat.

Animals↗