Drug metabolism in the newborn

The duration and intensity of drug action depend not only on the dose of the drug but also on the rates at which drugs are transformed to products that can be excreted readily by the kidney. Two general categories of drug metabolism occur in the liver: phase 1 reactions (oxidations-reductions and hydrolyses) and phase 2 reactions (synthetic conjugations). Phase 1 reactions produce functional groups that can participate in phase 2 reactions. Phase 1 reactions are almost nonexistent in the fetuses of laboratory animals; however, many appear in primates during the first trimester of gestation. Phase 2 reactions are deficient prenatally in both rodents and primates. Parturition triggers a surge of both phase 1 and phase 2 reactions. The lack of uniformity of the development of phase 1 oxidative reactions during the early neonatal period reflects the multiplicity of cytochrome P-450 hemoproteins, the terminal oxidases responsible for most hepatic oxidative biotransformations. The rate of recovery of chemically induced losses of cytochrome P-450 systems is age dependent.     

Polyamine metabolism in the Microsporidia

Members of the phylum Microspora are all obligate intracellular parasites. Little is known concerning metabolic pathways in these parasites, some of which pose serious problems in immunocompromised patients. We investigated polyamine metabolism in the systemic pathogen Enterocytozoon cuniculi using intact pre-emergent spores, and cell-free preparations. We found both polyamine synthetic and interconversion pathways to be operative, as evidenced by conversion of ornithine into polyamines, and production of spermidine from spermine by pre-emergent spores. Recent developments in the antitumour field have highlighted the ability of bis-ethylated polyamine analogues to reduce polyamine levels and block growth of tumour cells. In light of enhanced polyamine uptake in Enc. cuniculi, we have begun to study bis-aryl 3-7-3 and bis-ethyl oligoamine analogues as leads for chemotherapy of microsporidia.     

Inosine metabolism in the rat

1. Uptake and subsequent metabolism of purine and ribose moieties was monitored after intravenous administration of doubly labelled inosine. 2. More than 95% was cleared from the plasma within 5 min, and 99% within 20 min. 3. Approx. 50% of the 160 mumol total was rapidly incorporated into liver and kidney. Kidney removed the greatest amount (21 mumol/g wet wt.), about 10-fold more than heart, lung or liver. Lung and heart accounted for only 3%. These tissues then lost radioactivity during the remainder of the experiment. Radioactivity in the skeletal muscle, in contrast, increased from 8% of the injected dose at 5 min to 40% at 60 min. 4. In liver, kidney, heart and lung there was a significant difference in the fate of inosine. After initial incorporation of inosine, kidney predominantly lost inosine; heart preferentially lost purines; lung preferentially lost ribose radioactivity; and in liver the ribose radioactivity was rapidly lost, whereas purine was retained. Some of the ribose moiety was metabolized to glucose, presumably in the liver, and then released into the blood. Ribose radioactivity (probably as glucose) and radioactive hypoxanthine accumulated in skeletal muscle throughout the experiment. 5. Inosine caused a rapid and prolonged increase in the blood glucose content, from 6 to 15 mM in 60 min. This was accompanied by a small increase in plasma insulin. 6. It is concluded that the purine and ribose radioactivity lost from the kidney, liver and other tissues becomes incorporated into skeletal muscle.     

Iron metabolism in the yeast

Current data concerning transport, storage and utilization of iron in the yeast cells, particularly Saccharomyces cerevisiae are summarized in the paper. It has been marked that iron uptake in the cells provides by high affinity system, it function is carried out by protein complex Fet3-Ftr1, and Fet4, protein with low affinity to iron ion. The both systems utilize Fe(II). Furthermore, the active site of the protein Fre1 is exposed on the outer side of plasmalemma. This protein, due to ferrireductase activity, provides availability of Fe(III) to the cell. The information regards to participation of siderophores and metal-proton plasma membrane exchangers Smf1 in iron transport is brought. Particular attention is given to regulation of expression of the genes, coding the iron metabolic systems. Some aspects of iron utilization for Fe-S-containing enzymes synthesis are lighted. It has been concluded that the yeast is a perspective subject for studying balance of living organisms between iron essentiality and its ability to trigger free radical reactions.     

Dexamethasone metabolism in the horse

Dexamethasone and a metabolite, 9-fluoro-16α-methyl-6β, 11β, 16β-trihydroxy-1, 4-androstadiene-3, 17-dione, were detected in the urine of horses injected parenterally with the parent drug. The structure of the metabolite was elucidated by thin-layer chromatography, infrared spectroscopy, mass spectroscopy and nuclear magnetic resonance spectroscopy.     

Androgen metabolism in the dog

The metabolism of four androgenic compounds, testosterone (T), androstenedione (A), epitestosterone (epi-T) and testosterone glucuronide (T-gl) was studied in the dog. All were predominantly excreted via the biliary route, and since the urinary excretion in intact and biliary fistula dogs was similar, there was an apparent lack of any significant enterohepatic circulation. The metabolism of T was somewhat different from that of A, with indications that the bulk of T is converted to A. All four compounds were preponderantly excreted as glucuronides. Five metabolites of T in bile, i.e., epiandrosterone, eticholanolone and three epimeric androstanediols (5α/3β,17β; 5β/3α,17β and 5β/3β,17β) were identified. The first three compounds were also found to be metabolites of A. Epi-T underwent reduction (5α-androstane-3β,17β-diol) and hydroxylation in ring A and 17-hydroxy oxidation. Radioactivity associated with administered T-gl was eliminated rapidly from the body. Even though the 17α-androgens may be important in canine prostatic physiology, the present study points to the insignificance of the 17α-pathway in the systemic metabolism of T and A.     

Cholesterol metabolism in the brain

The central nervous system accounts for only 2% of the whole body mass but contains almost a quarter of the unesterified cholesterol present in the whole individual. This sterol is largely present in two pools comprised of the cholesterol in the plasma membranes of glial cells and neurons and the cholesterol present in the specialized membranes of myelin. From 0.02% (human) to 0.4% (mouse) of the cholesterol in these pools turns over each day so that the absolute flux of sterol across the brain is only approximately 0.9% as rapid as the turnover of cholesterol in the whole body of these respective species. The input of cholesterol into the central nervous system comes almost entirely from in situ synthesis, and there is currently little evidence for the net transfer of sterol from the plasma into the brain of the fetus, newborn or adult. In the steady state in the adult, an equivalent amount of cholesterol must move out of the brain and this output is partly accounted for by the formation and excretion of 24S-hydroxycholesterol. This cholesterol turnover across the brain is increased in neurodegenerative disorders such as Alzheimer's disease and Niemann-Pick type C disease. Indirect evidence suggests that large amounts of cholesterol also turn over among the glial cells and neurons within the central nervous system during brain growth and neuron repair and remodelling. This internal recycling of sterol may involve ligands such as apolipoproteins E and AI, and one or more membrane transport proteins such as members of the low density lipoprotein receptor family. Changes in cholesterol balance across the whole body may, in some way, cause alterations in sterol recycling and apolipoprotein E expression within the central nervous system, which, in turn, may affect neuron and myelin integrity. Further elucidation of the processes controlling these events is very important to understand a variety of neurodegenerative disorders.