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Biomedical subjects

J Meijer

Publications and source records attributed to J Meijer.

At least 73 records · Page 4Linked to original sources
PubMed1983

Comparison of trans-stilbene oxide, phenobarbital and 3-methylcholanthrene as inducers of steroid metabolism by the rat liver microsomal cytochrome P-450 system.

The metabolism of testosterone and androstenedione by liver microsomes was investigated after treatment of rats with trans-stilbene oxide, phenobarbital, or 3-methylcholanthrene. Conditions for linearity of the assay with time and amount of cytochrome P-450, as well as saturating substrate concentrations, were established. The metabolites were separated by thin-layer chromatography and quantitated by scintillation counting. The rates of formation of different testosterone and androstenedione metabolites after induction with trans-stilbene oxide or phenobarbital were similar, indicating that these xenobiotics induce the same isozyme of cytochrome P-450. This conclusion was further supported using inhibitors of cytochrome P-450 (SKF-525A, metyrapone and alpha-naphthoflavone) and with immunoinhibition by antibodies directed towards the phenobarbital-inducible form of cytochrome P-450. After treatment with trans-stilbene oxide or phenobarbital, the specific rates of formation of the 6 beta- and/or 2 beta-hydroxy metabolites and of 17 beta-hydroxy-4-androstene-3,16-dione were increased. In contrast, administration of 3-methylcholanthrene led to decreases in the specific rates of formation of almost all testosterone and androstenedione metabolites investigated. However, all three of these inducers cause increases in the total liver metabolism of testosterone and androstenedione. These increases are 2--30-fold in the case of trans-stilbene oxide, 3--46-fold for phenobarbital and 1--4-fold after treatment with 3-methylcholanthrene. The possible physiological significance of these effects is as yet unknown.

Androstenedione↗
PubMed1983

The risk of tuberculous infection in The Netherlands from 1967 to 1979.

Estimates of the annual risks of tuberculous infection in the Netherlands from 1910 to 1966 were made by Stýblo et al. [1] from tuberculin surveys in recruits and schoolchildren. The risk decreased particularly steeply after about 1940 (the annual decrease in log risk was about 13%), and forward projections of the risk were made on this basis to 1980. Tuberculin test results in male recruits and in secondary or primary schoolchildren between 1966 and 1979 have now been used, alone and in conjunction with the earlier material, to estimate the trend in the risk of tuberculous infection in the Netherlands up to 1979, and to study the sex and age patterns in the risk. The risk of infection has continued to decrease steeply with calendar year in the Netherlands. Among the recruits the log risk, estimated only from the data from 1966 to 1979, decreased annually by 10.4%, compared with the estimate of 13.7% from the earlier data from 1956 to 1966; this difference is non-significant. Analysis of the complete data on schoolchildren from 1956 to 1979 shows a decrease in their log risk of infection of 15.0% each calendar year. The risks of infection were similar for boys and girls up to age 10, but were higher for boys than for girls (by 10.2%) during adolescence. In addition there was an increase in log risk of about 6.1% for each year of age up to age 20. According to this analysis, the annual risks of tuberculous infection in 1979 in the Netherlands were estimated to be 6, 9, 12, and 16 in 100 000 boys aged 5, 10, 15 and 20 years respectively, and 6, 9, 11 and 15 in 100 000 girls.

Adolescent↗
PubMed1983

The persistence of tuberculin sensitivity following oral BCG vaccination in The Netherlands.

Certain anomalies in the tuberculin test results in Netherlands schoolchildren in the late 1960s and in recruits a few years later are shown to have arisen from the persistence of tuberculin sensitivity in some of the 10 000 newborn children who were given oral BCG vaccine in the early 1950s. More than 90% of these oral BCG vaccinations were given in 1950 or 1951 in Amsterdam, Delft or Hilversum, but because of the absence of a scar or any record, individuals who were vaccinated cannot now be distinguished from the much larger numbers of unvaccinated subjects. The cohorts of Dutch children born in 1950 and 1951 showed excess positivity, compared with earlier and later cohorts, when tuberculin tested at different ages in adolescence and as army recruits, and this was especially noticeable among current residents in these three cities. It is estimated that less than 10% of those given oral BCG vaccine in the Netherlands in 1950 or 1951 showed positive reactions at ages 12 and 13, but about 20% did at age 16, and about 45% at age 18. A review of data on tuberculin sensitivity several years after intradermal BCG vaccination in the newborn or in young children suggests that sensitivity persists in only a relatively small proportion for a long period (in perhaps about 45% after 7 years and less after a longer period), unless boosted by intervening tuberculin tests. The present data on oral BCG vaccination in the newborn conform to the same pattern.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1983

Characterization of the microsomal cytochrome P-450 species induced in rat liver by 2-acetylaminofluorene.

2-Acetylaminofluorene induces the level of cytochrome P-450 in rat liver microsomes by 50% (p less than 0.001). This induced cytochrome(s) was characterized and compared to the major forms of cytochrome P-450 induced by phenobarbital and 3-methylcholanthrene. The properties investigated were: the absorption maximum of the complex formed between reduced cytochrome P-450 and carbon monoxide; the substrate specificities using aminopyrine, benzphetamine, ethylmorphine, benzo(a)pyrene, ethoxycoumarin, ethoxyresorufin, and 2-acetylaminofluorene itself as substrates; metabolite patterns with benzo(a)pyrene and 2-acetylaminofluorene; sensitivity to different inhibitors; binding spectra with aniline and hexobarbital; and molecular weight as determined by sodium dodecyl sulfate:disc gel electrophoresis. The results indicate that 2-acetylaminofluorene induces a form(s) of cytochrome P-450 especially effective in the metabolism of this substance itself (i.e., the process can be called substrate induction) and different from the major forms of cytochrome P-450 induced by phenobarbital and 3-methylcholanthrene.

2-Acetylaminofluorene↗
PubMed1983

Electrical and pharmacological properties of the suprachiasmatic nuclei.

The suprachiasmatic nuclei (SCN) of the mammalian hypothalamus are in important circadian pacemaker. The electrical activity of these nuclei exhibits an intrinsic circadian rhythm. The rhythmicity of the SCN is also reflected in cyclic glucose consumption and serotonin metabolism. These rhythms are entrained to the light-dark cycle via the retinohypothalamic projection. This pathway, possibly together with a visual projection via the ventral lateral geniculate nuclei, innervates light-responsive SCN cells, which exhibit the functional properties of luminance detectors. The SCN contain various peptides, acetylcholine, and serotonin either intrinsically or in terminals of afferent projections. For acetylcholine it has been demonstrated that the SCN mediate the process of photic entrainment and light suppression of pineal synthetic activity. In the case of serotonin and vasopressin it seems certain that the SCN do not depend on their presence for generating circadian rhythms or for entrainment. Both substances may modulate the intrinsic pacemaker frequency through mechanisms that remain to be established.

Action Potentials↗
PubMed1982

Characterization of the microsomal cytochrome P-450 species induced in rat liver by trans-stilbene oxide.

trans-Stilbene oxide differs from the classical inducers of drug-metabolizing enzymes, phenobarbital and 3-methylcholanthrene, in that it induces the so-called phase II activities, epoxide hydrolase and glutathione S-transferase, to a much larger extent than it induces cytochrome P-450. Nonetheless, the level of cytochrome P-450 in liver microsomes from rats treated with trans-stilbene oxide is increased significantly to twice the control value. The existence of a number of different isozymes of cytochrome P-450 has now been clearly demonstrated and in the present study we have posed the question. What form(s) of cytochrome P-450 is induced by trans-stilbene oxide? A number of criteria including substrate specificity, pattern of benzo(a)pyrene metabolism, sensitivity to inhibitors, substrate binding spectra, ethylisocyanide binding spectra, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and crossed immunoelectrophoresis were used to answer this question. It seems clear that trans-stilbene oxide induces the same form(s) of cytochrome P-450 as phenobarbital.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1982

Purification of human liver cytosolic epoxide hydrolase and comparison to the microsomal enzyme.

Epoxide hydrolase (EC 3.3.2.3) was purified to electrophoretic homogeneity from human liver cytosol by using hydrolytic activity toward trans-8-ethylstyrene 7,8-oxide (TESO) as an assay. The overall purification was 400-fold. The purified enzyme has an apparent monomeric molecular weight of 58 000, significantly greater than the 50 000 found for human (or rat) liver microsomal epoxide hydrolase or for another TESO-hydrolyzing enzyme also isolated from human liver cytosol. Purified cytosolic TESO hydrolase catalyzes the hydrolysis of cis-8-ethylstyrene 7,8-oxide 10 times more rapidly than does the microsomal enzyme, catalyzes the hydrolysis of TESO and trans-stilbene oxide as rapidly as the microsomal enzyme, but catalyzes the hydrolysis of styrene 7,8-oxide, p-nitrostyrene 7,8-oxide, and naphthalene 1,2-oxide much less effectively than does the microsomal enzyme. Purified cytosolic TESO hydrolase does not hydrolyze benzo[a]pyrene 4,5-oxide, a substrate for the microsomal enzyme. The activities of the purified enzymes can explain the specific activities observed with subcellular fractions. Anti-human liver microsomal epoxide hydrolase did not recognize cytosolic TESO hydrolase in purified form or in cytosol, as judged by double-diffusion immunoprecipitin analysis, precipitation of enzymatic activity, and immunoelectrophoretic techniques. Cytosolic TESO hydrolase and microsomal epoxide hydrolase were also distinguished by peptide mapping. The results provide evidence that physically different forms of epoxide hydrolase exist in different subcellular fractions and can have markedly different substrate specificities.

Adolescent↗
PubMed1982

Preparation and characterization of subcellular fractions from the liver of the Northern Pike, Esox lucius.

The present study was designed to prepare and characterize subcellular fractions from the liver of the Northern pike (Esox lucius), with special emphasis on the preparation of microsomal fractions suitable for studying xenobiotic metabolism. The purity of the different fractions obtained by differential centrifugation, as well as the recovery of different organelles, was determined using both enzyme markers and morphological examination with the electron microscope. Attempts were also made to increase the recovery of fragments of the endoplasmic reticulum in the microsomal fraction. Finally, the subcellular distribution of several drug-metabolizing enzymes (cytochrome P-450, benzpyrene monoxygenase, epoxide hydrolase and glutathione transferases) were determined. With the exception of the subcellular distribution of epoxide hydrolase, the results obtained here resemble closely those reported fo rat liver and the microsomal fraction prepared is highly suitable for further studies of drug metabolism in pike liver.

Animals↗
PubMed1980

Measurement of drug-metabolizing systems in Salmonella typhimurium strains G46, TA15135, TA100, TA1538 and TA98.

Salmonella typhimurium strains which are commonly used in the Ames test for screening potential carcinogens were examined for a number of drug-metabolizing systems. Neither cytochrome P-450 itself nor two activities catalyzed by the cytochrome P-450 system in mammalian cells, i.e., benzpyrene monooxygenase and ethoxycoumarin O-deethylation, could be detected. Nor do these bacterial strains demonstrate any ability to detoxify epoxides by hydrating them or to conjugate p-nitrophenol with glucuronic acid. On the other hand, S. tryphimurium strains G46, TA1535, TA100, TA1538 and TA98 contain considerable amounts of acid-soluble thiols, approx. 5--10% of which is glutathione. These bacteria can also enzymatically conjugate glutathione with 1-chloro-2,4-dinitrobenzene (CDNB) and can reduce oxidized glutathione using NADPH as cofactor. Thus, enzymatic and non-enzymatic reaction of immediate carcinogens with thiol groups in s. typhimurium may have a significant effect on the outcome of the Ames test in certain cases.

Bacterial Proteins↗
PubMed1980

Characterization of rat-liver microsomal glutathione S-transferase activity.

Rat liver microsomes were shown to catalyze the conjugation of 1-chloro-2,4-dinitrobenzene with glutathione and this activity has been characterized. It cannot be removed from the microsomes by washing or other procedures which release loosely bound material from membranes. The microsomal glutathione S-transferase can be activated up to eight fold by treatment with N-ethylmaleimide. This activation also affects the apparent Km of the enzyme(s) for both glutathione and 1-chloro-2,4-dinitrobenzene. Upon subcellular fractionation of the liver the N-ethylmaleimide-activateable glutathione S-transferase distributes in the same manner as a marker for the endoplasmic reticulum and unlike markers for the other organelles and for the cytoplasm. Treatment of microsomes with proteases revealed that the enzyme is at least partially exposed on the cytoplasmic surface of the endoplasmic reticulum. Finally, three inducers of drug-metabolizing systems-i.e. phenobarbital, methylcholanthrene, and trans-stilbene oxide-all increase the activity of the cytoplasmic glutathione S-transferases, but they do not affect the microsomal activity. These and other considerations indicate that the microsomal glutathione S-transferase(s) is distinct from the cytoplasmic enzymes catalyzing similar reactions. The microsomal enzyme is likely to be involved in drug metabolism and the possibility of activating it through attack on a sulfhydryl group may represent an important physiological response to certain xenobiotics.

Animals↗