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At least 19 recordsLinked to original sources
PubMed1989

Metabolic inactivation of leukotrienes.

The metabolic inactivation of the cysteinyl leukotrienes LTC4 and LTD4 and of the chemotactic LTB4 was studied in the rat in vivo and in hepatocyte suspensions, respectively. 1. Deactivation of LTC4 via LTD4 to LTE4 was a most active process in the blood circulation, catalyzed mainly by ectoenzymes located on the internal wall of blood vessels. Uptake of cysteinyl leukotrienes by hepatocytes and kidney cells contributed to the rapid elimination of these potent mediators whenever they were released into the blood circulation. The initial half-life of LTC4 in vivo was 12 seconds. 2. omega-Oxidation leads to the formation of omega-hydroxylated and omega-carboxylated cysteinyl leukotrienes which were detected in bile and urine. Biliary metabolites included those formed by stepwise beta-oxidative degradation of omega-carboxy-N-acetyl-LTE4, yielding the dinor, tetranor, and hexanor derivative. 3. The peroxisome proliferator clofibrate strongly increased the degradation of LTE4 by omega-oxidation and subsequent beta-oxidation in vivo. The generation of new polar metabolites was detected by HPLC methods and by the use of 3H8-labeled cysteinyl leukotrienes in comparison with the 3H2-labeled precursor. 4. The metabolic degradation and inactivation of cysteinyl leukotrienes in vivo and of LTB4 in isolated hepatocytes was potently inhibited by ethanol. The site of inhibition was the oxidation of omega-hydroxy-N-acetyl-LTE4 and of omega-hydroxy-LTB4 to the respective omega-carboxylated metabolite. This inhibition led to an accumulation of the biologically active LTB4 and of N-acetyl-LTE4. The interference of leukotriene inactivation in the liver may provide a novel explanation for the ethanol-induced inflammatory reaction in acute alcoholic liver disease.

Animals↗
PubMed1991

Metabolic inactivation: a mechanism of human tumor resistance to bleomycin.

The mechanism of human tumor resistance to the antineoplastic drug bleomycin (BLM) is not known. We now provide evidence implicating metabolic inactivation in the resistance of human Burkitt's (Daudi) lymphoma to BLM. Daudi lymphoma and human head and neck squamous cell carcinoma (A-253) cells grown (s.c.) in nude mice were found to be resistant and sensitive to BLM treatment, respectively. Within 1 h of s.c. injection of [3H]BLM A2, Daudi xenografts accumulated less BLM and metabolized this drug to a much greater extent than did A-253 xenografts. The BLM-resistant Daudi xenografts metabolized BLM A2 to at least 6 metabolites and only a small proportion of the drug remained as unmetabolized BLM A2. In the BLM-sensitive A-253 xenografts, however, BLM A2 remained the major component. Incubation of BLM A2 with Daudi cytosolic fractions resulted in a complex mixture of metabolites similar to that formed by Daudi xenografts in nude mice. This BLM metabolite mixture was biologically inactive in plasmid DNA degradation assays. Treatment of mice bearing Daudi xenografts with an inhibitor of BLM hydrolase, L-trans-epoxysuccinyl-leucylamido-(4-guanidino)butane (E-64), prior to [3H]BLM A2 treatment did not affect the amount of BLM accumulated but inhibited BLM A2 metabolism in the xenografts. Furthermore, although E-64 alone did not inhibit the growth of Daudi xenografts, it potentiated the antitumor activity of BLM. These results indicate that Daudi tumors resist BLM by metabolically inactivating it and that inhibition of BLM metabolism in vivo enhances the antitumor activity of BLM and hence overcomes resistance.

Animals↗
PubMed1988

Rapid metabolic inactivation of tipredane, a structurally novel topical steroid.

[3H]Tipredane ([3H]TP), [3H]triamcinolone acetonide ([ 3H]TAAC), [3H]hydrocortisone ([3H]HC), and [3H]betamethasone-17 alpha-valerate ([3H]BMV), each at a concentration of 1 microM, were separately incubated with the 10,000 g supernatant fraction of the liver and skin homogenates of humans, rats and mice (BMV was studied only in human liver). Sequential samples were taken for up to 1 h during each incubation. The radioactivity in each sample was extracted with methanol, and the methanolic extracts were analyzed by high performance liquid chromatography. Among the four compounds studied, [3H]TP was most rapidly biotransformed by the liver preparations of the three species. The rates of in vitro biotransformation of TP were 2.5-30 times faster than those of TAAC, HC and BMV. In the human liver preparation, the rates of biotransformation were in the order of: TP greater than TAAC greater than HC = BMV. In the mouse and rat liver preparations, the orders were: TP greater than TAAC greater than HC and TP greater than HC greater than TAAC, respectively. In the skin preparations, little, if any, biotransformation of [3H]TP and [3H]TAAC was observed in any of the species studied; however, [3H]HC underwent a slow, steady biotransformation in the skin preparations of humans and rats but not of mice. [3H]TP was biotransformed by the liver preparations of all three species to numerous metabolites, thirteen of which have been identified. The biotransformation reactions included: (1) sulfoxidation; (2) elimination of either one or both alkylthio groups; and (3) hydroxylation of the steroid nucleus. Some metabolites were synthesized and tested for glucocorticoid receptor binding and anti-inflammatory activities; all were found to be much less potent than TP. The observed separation of local anti-inflammatory activity from systemic side effects of TP is most probably due to its rapid metabolic inactivation; the liver, rather than the skin, is mainly responsible for the metabolic inactivation of TP.

Androstadienes↗
PubMed2000

Metabolic inactivation of five glycidyl ethers in lung and liver of humans, rats and mice in vitro.

1. Some glycidyl ethers (GE) have been shown to be direct mutagens in short-term in vitro tests and consequently GE are considered to be potentially mutagenic in vivo. However, GE may be metabolically inactivated in the body by two different enzymatic routes: conjugation of the epoxide moiety with the endogenous tripeptide glutathione (GSH) catalysed by glutathione S-transferase (GST) or hydrolysis of the epoxide moiety catalysed by epoxide hydrolase (EH). 2. The metabolic inactivation of five different GE, the diglycidyl ethers of bisphenol A (BADGE), 4,4'-dihydroxy-3,3',5,5'-tetramethylbiphenyl (Epikote YX4000) and 1,6-hexanediol (HDDGE) and the GE of 1-dodecanol (C12GE) and o-cresol (o-CGE), has been studied in subcellular fractions of human, C3H mouse and F344 rat liver and lung. 3. All GE were chemically very stable and resistant to aqueous hydrolysis, but were rapidly hydrolysed by EH in cytosolic and microsomal fractions of liver and lung. The aromatic GE were very good substrates for EH. In general, microsomal EH is more efficient than cytosolic EH in hydrolysis of GE, and human microsomes are more efficient than rodent microsomes. 4. The more water-soluble GE, o-CGE and HDDGE, were good substrates for GST whereas the more lipophilic GE, YX4000 and C12GE, were poor substrates for GST. In general, rodents are more efficient in GSH conjugation of GE than humans. 5. In general, the epoxide groups of YX4000 are the most and those of HDDGE the least efficiently inactivated of the five GE under study. For the other three GE no general trend was observed: the relative efficiency of inactivation varied with organ and species. 6. The large variation in metabolism observed with five representative GE indicate that GE have variable individual properties and should not be considered as a single, homogenous class of compounds.

Adolescent↗
PubMed1983

Metabolic inactivation of noradrenaline in human placenta, umbilical cord and fetal membranes.

Metabolic inactivation of noradrenaline (NA) was studied in human placenta, umbilical vessels, Wharton's jelly and fetal membranes. Highest degradation capacity was observed in the placenta and fetal membranes, where the NA was inactivated by both monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). No MAO and COMT activity was found in the cord jelly and the activities in umbilical vessels were very low.

Catechol O-Methyltransferase↗
PubMedDate not supplied

Characteristics of the inhibition and metabolic inactivation of the yeast TRNA nucleotidyl transferase.

1. Yeast tRNA nucleotidyl transferase is inhibited by low molecular weight compounds present in cell-free extracts. The inhibition produced by the main component(s) is competitive with respect to ATP and is not prevented by metal chelating agents. The major component(s) has been partially purified. It is resistant to heat (90 degrees C, 5 min) and insensitive to digestion by alkaline phosphatase, snake venom phosphodiesterase and inorganic pyrophosphatase, indicating that it is not a nucleotide. 2. Besides the masking of the transferase activity in the crude extracts by the inhibitors, the enzyme is inactivated in nitrogen starved cells. The inactivation also occurs in yeast mutants lacking several proteases and is not prevented by inhibitors of yeast proteases. These results rule out extracellular proteolysis as the cause of inactivation and strength our previous observations on the metabolic inactivation of the transferase in response to nitrogen starvation.

Adenosine Triphosphate↗
PubMed1991

Pharmacokinetics of drugs that inactivate metabolic enzymes.

The pharmacokinetics of drugs that cause inactivation of metabolic enzymes were derived for the single-compartment model with linear elimination kinetics. A simple mechanism for suicide inactivation of enzyme by its substrate was used to model the relationship between elimination of drug and enzyme activity as a function of time. Three modes of administration were considered: a single bolus dose, repetitive bolus dosing, and continuous administration. Unlike capacity-limited drug elimination, a bolus dose would always give apparent linear kinetics. The apparent terminal half-life after a bolus dose was a simple function of the remaining elimination activity. Repetitive dosing would give a gradual increase in half-life until the steady-state elimination activity was achieved. The time to achieve steady-state drug levels with continuous administration of drug, or repetitive dosing, was prolonged by the enzyme inactivation process, and was dependent on the rates of elimination, enzyme inactivation, and the dosing rate. Interactions between drugs would occur due to a reduction in elimination activity if they share the inactivated enzyme pathway, and the magnitude of the effect would be characterized by the shift in the terminal half-life of elimination.

Cytochrome P-450 Enzyme Inhibitors↗
PubMed1980

Studies on metabolism and toxicity of styrene: III. The effect of metabolic inactivation by rat-liver S9 on the mutagenicity of phenyloxirane toward Salmonella typhimurium.

A comparative study on enzymic factors influencing the metabolic inactivation of phenyloxirane (styrene oxide), a major mutagenic metabolite of styrene in the liver, was carried out with respect to soluble glutathione S-transferase and microsomal epoxide hydratase in the 9000 X g supernatant fraction (S9) from a rat-liver homogenate. The mutagenic activity of phenyloxirane to Salmonella typhimurium TA100 was markedly reduced by S9 in the presence of glutathione but to a smaller extent in its absence. The retarding effect of glutathione on the inherent mutagenic activity of phenyloxirane was exerted by the soluble supernatant of S9 but not by microsomes. A gas-liquid chromatographic study indicated that the effect of glutathione was attributable to the disappearance of the mutagen from the microbial assay system. The rate of the disappearance was 10-20 times as fast in the soluble supernatant fraction as in the microsomes when fortified with more than 4 mM glutathione. Our results strongly suggest that in hepatic cells of the rat, cytosol glutathione S-transferase plays a much more important role than microsomal epoxide hydratase in the detoxication of the metabolite, phenyloxirane.

Animals↗
PubMed1988

Cerebral perfusion of metabolic inactivators: a new method for rapid fixation of labile lipid pools in brain.

This paper describes a new method for the rapid fixation of labile lipid pools in the brain. Perfusion of the brain with 0.9% saline containing esterase inhibitors (p-bromphenacyl-bromide and diisopropyl fluorophosphate), an antioxidant (nordihydroguaiaretic acid) and a Ca2+ chelator (EDTA) resulted in a substantial reduction in the levels of free fatty acids, a biochemical marker for the degradation of labile membrane lipids. Levels of unesterified polyunsaturated fatty acids in whole brain were decreased by 90-96% as compared to levels in brains perfused with saline alone. Levels of docosahexaenoic acid approximated levels obtained after microwave irradiation. Unlike microwave irradiation, this perfusion technique perserves the cellular structure of the brain, thereby allowing subcellular fractionation with minimal postmortem changes in lipid pools. The release of arachidonic acid during isolation of the P2 (synaptosomal) fraction was completely inhibited by the presence of the metabolic inactivators. The results of this study demonstrate a new and useful technique for the postmortem inactivation of enzymes responsible for the degradation of labile lipids in the brain. Further, the data underscore the key role of phospholipase A2 and Ca2+ in mediating the release and accumulation of free fatty acids in the ischemic brain.

Animals↗
PubMed1996

Two Gs-coupled prostaglandin E receptor subtypes, EP2 and EP4, differ in desensitization and sensitivity to the metabolic inactivation of the agonist.

There are at least four subtypes of prostaglandin E (PGE) receptors. The EP1 and EP3 receptors are coupled to Ca2+ mobilization and the inhibition of adenylate cyclase, respectively, and the EP2 and EP4 receptors are coupled to the same signal transduction pathway, stimulation of adenylate cyclase. To identify the functional differences between EP2 and EP4 receptors, we examined agonist-induced desensitization of these two receptors using Chinese hamster ovary cells, which stably express these receptors. The EP4 receptor underwent short term agonist-induced desensitization, but no such desensitization was observed for the EP2 receptor. In contrast, the EP2 and EP4 receptors displayed similar patterns of down-regulation in response to prolonged exposure to PGE2. On the other hand, PGE2 is rapidly metabolized to 15-keto-PGE2 and, subsequently, to 13,14-dihydro-15-keto-PGE2. Thus, we compared the sensitivities of the two receptors to these two metabolites. The EP4 receptor markedly lost the response at the first metabolism, whereas the EP2 receptor gradually lost the response according to the degree of metabolism, having higher sensitivity to the first metabolite, 15-keto-PGE2, than the EP4 receptor. Therefore, the physiological significance of EP2 and EP4 may lie in their different sensitivities to agonist-induced short term desensitization and their differential susceptibilities to the metabolic inactivation of the agonist.

Animals↗
PubMed2006

Metabolic inactivation of resolvin E1 and stabilization of its anti-inflammatory actions.

The resolvins (Rv) are lipid mediators derived from omega-3 polyunsaturated fatty acids that act within a local inflammatory milieu to stop leukocyte recruitment and promote resolution. Resolvin E1 (RvE1; (5S,12R,18R)-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid) is an oxygenase product derived from omega-3 eicosapentaenoic acid that displays potent anti-inflammation/pro-resolution actions in vivo. Here, we determined whether oxidoreductase enzymes catalyze the conversion of RvE1 and assessed the biological activity of the RvE1 metabolite. With NAD+ as a cofactor, recombinant 15-hydroxyprostaglandin dehydrogenase acted as an 18-hydroxyl dehydrogenase to form 18-oxo-RvE1. In the murine lung, dehydrogenation of the hydroxyl group at carbon 18 position to form 18-oxo-RvE1 represented the major initial metabolic route for RvE1. At a concentration where RvE1 potently reduced polymorphonuclear leukocyte (PMN) recruitment in zymosan-induced peritonitis, 18-oxo-RvE1 was devoid of activity. In human neutrophils, carbon 20 hydroxylation of RvE1 was the main route of conversion. An RvE1 analog, i.e. 19-(p-fluorophenoxy)-RvE1, was synthesized that resisted rapid metabolic inactivation and proved to retain biological activity reducing PMN infiltration and pro-inflammatory cytokine/chemokine production in vivo. These results established the structure of a novel RvE1 initial metabolite, indicating that conversion of RvE1 to the oxo product represents a mode of RvE1 inactivation. Moreover, the designed RvE1 analog, which resisted further metabolism/inactivation, could be a useful tool to evaluate the actions of RvE1 in complex disease models.

Animals↗
PubMed1994

Catechol-O-methyltransferase-catalyzed rapid O-methylation of mutagenic flavonoids. Metabolic inactivation as a possible reason for their lack of carcinogenicity in vivo.

Quercetin is highly mutagenic in vitro, yet is not carcinogenic when administered chronically at large doses to rodents for 12 months. We hypothesized that catechol-O-methyltransferase-catalyzed O-methylation of quercetin and other mutagenic catechol-containing flavonoids may provide an efficient inactivation in vivo and may therefore prevent tumor induction by these flavonoids. After one intraperitoneal administration of 50 mg/kg quercetin to hamsters, a urinary ether extract contained 2% quercetin and 97% 3'-O-methylquercetin. When the urine was treated first with beta-glucuronidase and sulfatase, 13% quercetin and 87% 3'-O-methylquercetin were recovered. Quercetin was rapidly O-methylated by either porcine liver or hamster kidney catechol-O-methyltransferase, with Km values of 6.1 and 6.9 microM and Vmax values of 14,870 and 200 pmol/mg of protein/min, respectively. S-Adenosyl-L-homocysteine exhibited a potent feedback inhibition of the catechol-O-methyltransferase-catalyzed O-methylation of quercetin by a competitive mechanism with respect to S-adenosyl-L-methionine and by a competitive plus noncompetitive mechanism with respect to the substrate. A comparison of the O-methylation rates and kinetic characteristics (Km, Vmax, and Vmax/Km) demonstrated that rates of O-methylation of quercetin and fisetin were up to three orders of magnitude higher than those of catechol estrogens and catecholamines. In conclusion, the rapid metabolic inactivation of mutagenic flavonoids catalyzed by catechol-O-methyltransferase may be a major reason for the lack of their carcinogenic activities in vivo.

Animals↗