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Results for “partial biotransformation”

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At least 19 recordsLinked to original sources
PubMed2026

Broad-spectrum biodegradation of aliphatic and aliphatic-aromatic polyesters by Papiliotrema laurentii isolated from locust frass.

Biodegradable aliphatic and aliphatic-aromatic polyesters, such as poly(butylene adipate-co-terephthalate) (PBAT), polylactic acid (PLA), polycaprolactone (PCL), polybutylene succinate (PBS), and polyhydroxyalkanoates (PHA), are increasingly used as sustainable alternatives to petrochemical plastics. However, their depolymerization outside industrial composting facilities is often incomplete. This study characterized Papiliotrema laurentii strain 62UF-13, isolated from migratory locust frass, for broad-spectrum polyester hydrolysis. Emulsion assays demonstrated hydrolytic activity across all five polymers, with PCL and PBS showing the highest clearance rates. Solid-film assays revealed substantial gravimetric mass loss of PCL, PLA, and PHA cast films, whereas a commercial PBAT-PLA mulch film in minimal medium, underwent progressive fragmentation/disintegration, as assessed by the remaining film area. Incubation with the PBAT-PLA film was accompanied by the release of adipic acid (49.60 mg/L, week 1) and terephthalic acid (maximum 21.62 mg/L, week 4), followed by a decrease to 0.26 mg/L by week 8, coinciding with the emergence of putative 3,4-dihydroxymandelic acid and a putative acetylated derivative. Scanning electron microscopy (SEM) revealed pronounced pitting and erosion, while Fourier-transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) indicated ester-bond scission and changes in crystallinity/melting behavior. Whole-genome sequencing identified eight candidate polyesterases, including cutinases and esterases, with ≥ 60% amino acid identity to known hydrolases active on PCL, PBS, PHA, and PLA. This study is the first report of P. laurentii degrading a broad range of aliphatic and aliphatic-aromatic polyesters, including partial biotransformation of terephthalate moieties from PBAT. Integration of phenotypic assays and genomic evidence positions P. laurentii 62UF-13 as a viable biocatalyst for decentralized management of biodegradable plastic waste under mild environmental conditions.

Papiliotrema laurentii↗
PubMed1977

[Prostaglandins and bronchial asthma (author's transl)].

Prostaglandins (PG) show different effects on the bronchomotoric excitability depending on the fact to which group they certain. The best investigated PG are PGE1, PGE2 (bronchodilators) and PGF2a (bronchoconstrictor). It is possible that PG play a certain role in the pathogenesis of bronchial asthma. Among other hypotheses, the influence upon adenylate cyclase - cAMP systems (without affecting the adrenoreceptors) is evident. Probably, PG exert a regulatory function on bronchial tone. The pathogenetic imporatnce of PG metabolites for bronchial asthma is discussed. A therapeutical influence upon bronchial asthma is theoretically possible on four ways: by 1) stimulation of partial endogenous synthesis of PGE, 2) inhibition of the biotransformation of PGE, 3) exogenous application of PGE, i.e. development of PGE derivatives indifferent to bronchial mucosa, stable in solution and relatively resistant to biotransformation and 4) inhibition of biosynthesis of PGF2a. The development of synthetic PGE1 derivatives (15-methyl-11-desoxy-PGE1) appears to be of future importance. Summarizing we can say that, at the present stage of development, a directed therapeutic utilization of PG for bronchial asthma seems to be of low probability yet. The problem of aspirin-induced asthma including all its practical consequences is discussed.

Asthma↗
PubMed1978

Identification of metabolites of valproic acid in serum of humans, dog, rat, and mouse.

In kinetic studies of VPA in humans, dogs, rats, and mice, as well as in clinical routine analysis of serum concentrations of VPA in epileptic patients, 2--4 peaks (depending on the species examined) were regularly found in the gas chromatograms in addition to VPA. Comparison with control serum indicated that these peaks resulted from metabolism of VPA. By GC--MS, two of these metabolites could be identified as 5-hydroxy-2-propyl-pentanoic acid (5-OH-VPA) and 4-hydroxy-2-propyl-pentanoic acid (4-OH-VPA), using synthesized reference substances. Both metabolites results from omega (omega1, omega2) oxidation of VPA, 5-OH-VPA only occurring in serum of mice, and 4-OH-VPA in serum of mice and humans. With the aid of low- and high-resolution mass spectra, likely structures of the two remaining metabolites, both of which were found in serum of all the species examined, were proposed. One of these, 3-hydroxy-2-propyl-pentanoic acid (3-OH-VPA) confirms the involvement of beta-oxidation in the metabolism of VPA. The fourth metabolite, whose identity is uncertain, indicates a substance not described previously as a metabolite of VPA.

Adolescent↗
PubMed1976

The pharmacokinetic characteristics of beta-receptor antagonists in man--similarities and differences of clinical relevance.

The aliphatic partial structure common to the beta-receptor antagonists leads to similar products of their biotransformation. The main qualitative and quantitative differences of the metabolism of the compounds of this class, however, rest in the nature of their aromatic or heterocyclic substituents. The physico-chemical properties of the beta-blockers appear to be predominantly responsible for the extent of metabolic degradation and for the distribution in the body, especially for the binding to proteins. As a consequence of their different biological disposition the clinically relevant systemic bioavailabilities of the various beta-blockers from oral doses differ drastically. Practolol maintains an extreme position among all other compounds: It is most hydrophilic, it is not bound to proteins, it is metabolized least, but cleared renally in unchanged form to 85% of the dose. Despite its extremely high systemic bioavailability, relatively high daily doses were required for therapy. The receptor sensitivity for practolol has been rated 2 to 3 powers of 1- lower than of propranolol. Comparative pharmacokinetic assessment of beta-receptor antagonists requires quantitative analytical data in clinically representative groups of patients. This has been demonstrated by respective studies with oxprenolol. The intra- and inter-individual systemic bioavailability, the differential analysis of plasma and erythrocytes, the multiexponential elimination kinetics, and their possible dependence on the dose have been studied as clinically relevant pharmacokinetic characteristics. The continuing attempt of the pharmaceutical industry to optimize the properties of beta-blockers also has taken advantage of the slow release principle in oral dosage forms as shown by the example of oxprenolol. The beta-receptor antagonists belong to one of the youngest classes of pharmaceuticals. Pharmacokinetic and metabolic data for the different representatives of this class have been generated in different laboratories with different approaches and different techniques. Therefore, full comparative documentation is still incomplete.

Adrenergic beta-Antagonists↗
PubMed1979

Pharmacokinetics of dipyridamole.

Dipyridamole, though originally introduced as a coronary vasodilator, has lately been increasingly investigated in the treatment of thromboembolic diseases because of its inhibitory influence upon blood platelet function. The compound is eliminated from the organism by hepatic biotransformation to the monoglucuronide, which almost exclusively is subjected to biliary and faecal excretion with simultaneous partial enterohepatic circulation taking place. Only minute amounts are excreted through the kidneys. In experiments on four normal human volunteers it was found that the serum concentration curve after intravenous administration of dipyridamole rather closely fits the pharmacokinetics of an open two-compartment model with first order, linear disposition kinetics and elimination taking place from the central compartment. Experiments with oral ingestion of the compound could be described by the use of a corresponding pharmacokinetic model with two consecutive first order input steps, representing the dissolution and absorption processes. The disposition rate constants (beta) were within the range of 0.0051--0.0083 min.-1 corresponding to biological half-lives of 84--145 min. The absorption rate constant was about 0.07 min.-1, and the systemic availability of an oral dose of 100 mg dipyridamole in tablets varied from 37 to 66%.

Administration, Oral↗
PubMed1979

Uptake and clearance of inhalation anesthetics in man.

The uptake, distribution, and clearance of inhaled vapors is governed by rules of partial pressure equilibration in a multicompartmental system. Since halogenated anesthetic agents are not soluble in water, biotransformation is their only clearance pathway during anesthesia. When apparent steady state is reached, the rate of overall metabolism can be determined from the pulmonary uptake rate. As a result of metabolism, pulmonary uptake increases but the concentration of inhaled vapor in blood and tissues decreases, and only a fraction of uptake is exhaled following anesthesia. Uptake and pulmonary clearance of five halogenated anesthetic agents were studied in 45 surgical patients. The susceptibility to biotransformation increases in the following order: isoflurane, enflurane, halothane, fluroxene, methoxyflurane.

Anesthesia, Inhalation↗
PubMedDate not supplied

Biotransformation of cannabidiol in mice. Identification of new acid metabolites.

The in vivo metabolism of cannabidiol (CBD) was investigated in mice. Following the ip administration of CBD to mice, livers were removed and metabolites were extracted with ethyl acetate prior to partial purification on Sephadex LH-20 columns. Fractions from the columns were converted into trimethylsilyl, d9-trimethylsilyl, and methylester-trimethylsilyl derivatives for analysis by gas-liquid chromatography-mass spectrometry. In addition, metabolites containing carboxylic acid and ketone functional groups were reduced to alcohols with lithium aluminum deuteride before trimethylsilation. A total of 22 metabolites were characterized, 14 of which had not been reported previously. The metabolites could be categorized as follows: monohydroxylated (N=2), dihydroxylated (N=3), CBD-7-oic acid, side chain hydroxy-GBD-7-oic acids (N=3), side-chain acids (N=3), 7-hydroxy-side-chain acids (N=4), 6-oxo-side-chain acids (N=3) and glucuronide conjugates (N=3). The most significant biotransformations were glucuronide conjugation and, to a lesser extent, formation of CBD-7-oic acid.

Animals↗
PubMed1976

Sex differences in anaesthetic toxicity: fluroxene and trifluoroethanol in mice.

A sex difference in postanaesthetic mortality after fluroxene anaesthesia was found in Swiss Webster mice. More males succumbed than females. This toxicity was biotransformation-dependent and could be reversed by pretreatment with "opposite" sex hormones. The toxicity of the fluroxene metabolite trifluoroethanol also was more marked in male mice, but was only partially influenced by microsomal enzyme inhibitors or stimulators, or by sex hormones.

Animals↗
PubMed1979

Changes in the molecular composition of circulating hydroxyethyl starch following consecutive daily infusions in man.

1 Changes in the circulating molecular composition of hydroxyethyl starch (HES) were determined in four normal men following three consecutive daily 500 ml infusions (total 1,500 ml), by passage of trichloroacetic acid filtrates of plasma through a Sepharose CL4B gel filtration column. 2 The HES recovered from the intravascular space 10 min following the injection on Days 1, 2 and 3, was of a narrower molecular size distribution than the injected material, with a noticeable shift to molecules of a low molecular weight (LMW) size. 3 The HES in the sampled plasma 24 h post-injection on Days 1, 2 and 3 consisted of molecules possessing a LMW distribution, concomitantly with a slight shift to molecules of a larger molecule size. 4 The HES recovered from the bloodstream 480 h after the third and final injection consisted of molecules possessing an intermediate size distribution, between LMW and high molecular weight (HMW) size material. 5 The results indicate that large HES molecules contained in the injected material are eliminated from the bloodstream; the HMW fraction at least partially by a alpha-amylase mediated catabolism, and the resulting LMW fraction by excretion.

Adult↗
PubMed1978

Induction of colon tumors in 1,2-dimethylhydrazine-resistant Lobund Wistar rats by methylazoxymethanol acetate.

Sprague-Dawley and Lobund Wistar rats, which were sensitive and resistant to induction of colon tumors by 1,2-dimethylhydrazine (DMH), respectively, were treated with methylazoxymethanol (MAM), the product of DMH metabolism by the microsomal mixed-function oxidase system. Although the colon tissue in both stocks of rats had similar NAD+-dependent dehydrogenase activities that are considered necessary to activate MAM to an ultimate carcinogen, still a sevenfold greater incidence of colon tumors was found in the Sprague-Dawley rats, and their tumors were more extensive. The results indicated that the difference in susceptibility to colon tumor induction between the rat stocks was partially related to metabolic activation of the DMH and to other, as yet undetermined, endogenous factors.

Adenocarcinoma↗
PubMed1978

Paradoxical effects of cobaltous chloride and salts of other divalent metals on tissue levels of reduced glutathione and microsomal mixed-function oxidase components.

Treatment of animals with cobaltous chloride caused decreases in hepatic, pulmonary and renal cytochrome P-450, and alterations in levels of other components of microsomal mixed-function oxidases, which can alter the rate of biotransformation of certain drug substrates. The treatment also caused a striking, dose-dependent elevation in tissue levels of reduced glutathione (GSH), within 2 to 8 hours. The effect of cobalt on GSH occurred in all tested animal species and strains. Actinomycin-D partially prevented the cobalt-stimulated rise in hepatic GSH. Salts of several other divalent metals also produced sharply elevated levels of hepatic GSH, occurring concomitantly with decreased microsomal content of cytochrome P-450. These results suggest that pretreatment of animals with cobaltous chloride, or other divalent metal salts, could alter the disposition of certain toxic, alkylating drug metabolites not only by decreasing the rate of formation of the reactive metabolites, but also by increasing the amount of GSH available for the formation of their less reactive, less toxic, GSH conjugates.

Animals↗
PubMedDate not supplied

The biotransformation of p-xylene to a toxic aldehyde.

Rats given a single ip injection of p-xylene suffered 65% loss of pulmonary microsomal p-xylene hydroxylase activity. The activity was protected by pretreating the rats with phenobarbital, which increased hepatic p-xylene hydroxylase and cytosolic aldehyde dehydrogenase activities, but had no effect on alcohol dehydrogenase activity in hepatic cytosol. Pretreatment of rats with pyrazole caused a 60% inhibition of liver alcohol dehydrogenase but had no effect on liver aldehyde dehydrogenase activity. This treatment partially protected the pulmonary microsomal p-xylene hydroxylase from inactivation by p-xylene. Experiments in vitro showed that inactivation of cytochrome P-450 by p-xylene required the metabolic conversion of p-xylene to p-tolualdehyde. The reactive intermediate (p-tolualdehyde) required the presence of NADPH to carry out the inactivation. Inasmuch as lung tissues cannot form p-tolualdehyde (because of the low activity of p-methylbenzyl alcohol dehydrogenase), it is assumed that the inactivation of lung enzymes in vivo following exposure to p-xylene was due to the aldehyde intermediate which is formed in the liver and transported to the lung.

Aldehydes↗
PubMed1978

Disposition and metabolism of 1-(tetrahydro-2-furanyl)-5-fluorouracil (ftorafur) in humans.

The pharmacology of high-dose 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT) has been studied by radiochemical and chromatographic techniques in eight patients. Plasma disappearance of FT was exponential, with a half-life of 8.8 hr. Plasma concentrations of 5-fluorouracil (FUra) were sustained at 12.8 nmol/ml (1.7 microgram/ml) for at least 48 hr after FT administration. The concentrations of FUra derived from the administration of FT were considerably greater than were those achieved by constant infusion of FUra at the maximal tolerated dose of 1.1 g/sq m without causing unacceptable mucositis. The cumulative urinary excretion was 20% of the administered dose in 24 hr. FT underwent in vivo biotransformation to 2 hydroxytetrahydrofuranyl-5-fluorouracil derivatives in addition to anabolites and catabolites of FUra. High concentrations of FT and FUra were present in the cerebrospinal fluid, which could account for the severe central nervous system toxicity of FT at high doses. We conclude that the antitumor activity of FT is partially attributable to its slow release of FUra.

Animals↗
PubMed1979

Biotransformation of chloroform by rat and human liver microsomes; in vitro effect on some enzyme activities and mechanism of irreversible binding to macromolecules.

The effects of chloroform on some rat microsomal enzyme activities were studied in vitro. Maximum inhibition of oxygen consumption, NADPH oxidase and NADPH-cytochrome c reductase was observed at 0.5 mM chloroform; prior metabolization of CHCl3 by microsomal monooxygenases increased inhibition by about 50% at 0.2-0.5 mM chloroform. Higher concentrations produced a paradoxical reversal of inhibition, whereas p-nitroanisole demethylase was steadily inhibited by about 50% up to 10 mM chloroform. Irreversible binding of 14CHCl3 was confirmed to depend on chloroform metabolization by monooxygenases. The increased irreversible binding due to phenobarbital induction is accompanied by a diminished affinity towards chloroform as shown by increased KM of irreversible binding, and a higher spectral dissociation constant KS. Aminoacids with nucleophilic functions (histidine, cysteine) partially prevented the irreversible binding of chloroform metabolites to microsomes; non-volatile radioactive derivatives were recovered in trichloracetic acid supernatants when microsomes were incubated with cysteine, but not with histidine. Phosgene has been demonstrated as a biological metabolite of chloroform: its possible reactions with nucleophilic groups of macromolecules, water and added aminoacids partly explain these experimental data. Similar results were obtained with human microsomes, showing that chloroform hepatotoxicity in man could involve the same mechanisms.

Animals↗
PubMed1979

Biotransformation of xenobiotics in human intestinal mucosa.

Drug-metabolizing enzymes, especially monooxygenases, play a major role in biotransformation and detoxification of many foreign compounds including environmental carcinogens. Although largely localized in the liver they are also found in the small intestine, which is the portal of entry of dietary toxins. Therefore cytochrome P-450 content as well as monooxygenase (7-ethoxycoumarin O-deethylase) and NADPH-cytochrome c reductase activities were determined in surgical specimens of the human small intestine and in jejunal biopsy material obtained from patients by use of a hydraulic biopsy instrument. Microsomes were prepared from surgical material; these ranged in P-450 content from 30 to 120 pmole/mg protein and in monooxygenase activity from 60 to 110 pmole/min-mg protein. In the 20,000g supernatant of the homogenized biopsy material, monooxygenase activity was undetectable in patients who had total villous atrophy, and low enzyme rates were found when the mucosa showed a partial villous atrophy. The mucosal monooxygenase activity of patients with normal jejunal histology and steatorrhea was significantly higher than in mucosa with villous atrophy but was only half of that observed in normal controls. These eight control patients had normal histology and no malassimilation. Our results suggest that monooxygenase activity in the human small intestine is dependent on the morphological integrity of the mucosa and that in normal mucosa the enzyme rates are reduced when malassimilation is present.

Animals↗
PubMedDate not supplied

Identification of some human urinary metabolites of orally administered potassium canrenoate by stable isotope-labeling techniques.

A single oral dose (200 mg) of an equimolar mixture of potassium canrenoate and its 20,20,21,21-tetradeutero analogue was administered to three healthy men. The steroids in urine collected for 24 hr after dosage were isolated on XAD-2 resin, and purified and fractionated into groups by lipophilic gel chromatography before and after hydrolysis of conjugates. GC/MS analysis of these fractions allowed the detection and identification of canrenone, canrenoic acid and its ester glucuronide, 3 beta-hydroxy-3-deoxocanrenone, 3beta-hydroxy-4,5alpha-dihydro-3-deoxocanrenone and a 3epsilon-hydroxy-4,5,6,7-tetrahydro-3-deoxocanrenone. In addition a number of di- and trihydroxy compounds formed by reduction and hydroxylation were partially identified from their E1 and C1 mass spectra. The results provide information on the metabolism of oral potassium canrenoate in man, and demonstrate the utility of combining stable isotope labeling, lipophilic gel chromatography, and GC/MS in studies of steroidal spirolactones.

Administration, Oral↗
PubMed1979

Caffeine metabolism in the newborn.

The concentrations of caffeine and metabolites in urine have been examined as a function of age to explore the remarkably slow elimination of caffeine by human infants. Urine samples were obtained from 3 adults and 10 infants aged 8 days to 8 months during therapeutic treatment with caffeine. A high-performance liquid chromatographic (HPLC) procedure involving reversed-phase partition chromatography was developed to separate caffeine and 13 of its metabolites. During the first month of life, caffeine accounted for more than 85% of the identifiable products in urine. Caffeine remained the predominant component for the first 3 months, but its percentage decreased gradually to the adult value of less than 2% by the age of 7 to 9 months. This change reflected increasing metabolite production, not decreasing urinary caffeine concentration. The adult metabolite pattern of partially demethylated xanthines and urates was attained by 7 to 9 months. The data indicate that the 4-day plasma t1/2 of caffeine characteristic of the newborn depends in large part on slow urinary excretion of unchanged drug since there is little or no metabolism. Subsequent decrease in the t1/2 to about 4 hr by the age of 8 months correlates closely with the rise in metabolite production.

Adult↗