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Biomedical subjects

A C Swart

Publications and source records attributed to A C Swart.

At least 19 recordsLinked to original sources
PubMed2002

Baboon CYP11B1: the localization and catalytic activity in baboon adrenal tissue.

A third gene encoding baboon CYP11B1 was isolated and was shown to catalyze only the metabolism of deoxycorticosterone (DOC) to corticosterone. The investigation into the localization of CYP11B1 in the baboon adrenal tissue, using in situ hybridization, showed that mRNA transcripts were predominantly present in the zona reticularis (ZR) and zona fasciculata (ZF). Signal was also observed in the zona glomerulosa (ZG) and scattered within the medulla. Immunohistochemical studies, using rabbit anti-sheep CYP11B1 IgG, indicated that CYP11B1 was expressed only in the zona fasciculata, zona reticularis and in the medulla. CYP11B1 was not detected in the zona glomerulosa. Subsequent Western Blot investigations into the presence of CYP11B1 in baboon adrenal cortex and medullary homogenates indicated CYP11B1 as a single band in the cortex and as two distinct bands in the medulla. CYP11A was present only in the baboon adrenal cortex. The metabolism of deoxycorticosterone and corticosterone was subsequently investigated in the baboon adrenal cortex and medulla. In cortex homogenates, deoxycorticosterone was converted to corticosterone, and neither 18-hydroxycorticosterone nor aldosterone was detected. In medulla homogenates, however, corticosterone was metabolized to aldosterone, as confirmed by APcI-MS.

Adrenal Glands↗
PubMed2000

Inhibition of cytochrome P450c11 by biogenic amines and an aziridine precursor, 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride.

The interaction of several biogenic amines and Compound A (2-(4-acetoxyphenyl)-2-chloro- N-methyl-ethylammonium chloride), an analogue of the active substance in a HPLC fraction isolated from the shrub, Salsola tuberculatiformis Botsch., with cytochrome P450c11 was investigated. Noradrenaline, octopamine and Compound A inhibited the type I DOC induced difference spectrum of P450c11 and elicited a type II difference spectrum when added alone. The Ks-values for noradrenaline, octopamine, and Compound A were 0.8 mM, 0.16 mM and 0.36 mM, respectively. Dopamine, adrenaline and synephrine did not interact with, or inhibit, P450c11. Further investigation of Compound A indicated that it is a mixed inhibitor of sheep P450c11 with a stronger competitive (Kic = 106-110 microM) than uncompetitive (Kiu = 667-737 microM) element, and that it inhibits the conversion of deoxycorticosterone to corticosterone by human 11beta-hydroxylase and aldosterone synthase with EC50 values of 97 microM and 190 microM, respectively, in fetal calf serum.

Acetates↗
PubMed2000

Baboon cytochrome P450c11 is encoded by more than one gene.

Two P450c11 genes, sharing 99% homology, were cloned from Cape baboon adrenal tissue using RT-PCR. The cDNAs showed 96% and 94.6% sequence identity to human P450c11 and aldosterone synthase, respectively. One of the gene sequences contained a termination codon in exon one. The cloned cDNAs were expressed in COS 1 cells and the metabolism of deoxycorticosterone to corticosterone investigated. The expressed enzyme exhibited 1 beta hydroxylase activity, but no aldosterone synthase activity.

Adrenal Glands↗
PubMed1998

Delayed sleep phase syndrome: A placebo-controlled cross-over study on the effects of melatonin administered five hours before the individual dim light melatonin onset.

In a double-blind placebo-controlled cross-over study, 30 patients with Delayed Sleep Phase Syndrome (DSPS) were included, of whom 25 finished the study. Melatonin 5 mg was administered during two weeks in a double-blind setting and two weeks in an open setting successively or interrupted by two week of placebo. The study's impact was assessed by measurements of the 24-h curves of endogenous melatonin production and rectal temperature (n = 14), polysomnography (n = 22), actigraphy (n = 13), sleep log (n = 22), and subjective sleep quality (n = 25). Mean dim light melatonin onset (DLMO) (+/- SD), before treatment, occurred at 23.17 hours (+/- 138 min). Melatonin was administered five hours before the individual DLMO. After treatment, the onset of the nocturnal melatonin profile was significantly advanced by approximately 1.5 hour. Body temperature trough did not advance significantly. During melatonin use, actigraphy showed a significant advance of sleep onset and polysomnography, a significant decreased sleep latency. Sleep architecture was not influenced. During melatonin treatment patients felt significantly more refreshed in the morning. These results show that analysis of DLMO of patients suffering from DSPS is important both for diagnosis and therapy. These results are discussed in terms of the biochemistry of the pineal.

Adult↗
PubMed1998

Melatonin-responsive headache in delayed sleep phase syndrome: preliminary observations.

The occurrence of headache and its change after treatment with melatonin 5 mg were studied in 30 patients with delayed sleep phase syndrome. The medication was taken 5 hours before the endogenous nocturnal plasma melatonin concentration had reached 10 pg/mL. Three women (aged 14, 14, and 23 years) suffered from chronic tension-type headache. Their headache disappeared within 2 weeks after the start of treatment with melatonin. One 54-year-old man suffered from disabling migraine attacks without aura, twice a week. After starting melatonin treatment, only three migraine attacks were reported in 12 months. Ever since his 40s, a 60-year-old man complained of cluster headache episodes lasting about 2 months, twice a year. In the year since starting melatonin treatment, only one 5-day cluster episode occurred. Nocturnal melatonin secretion in the patients with delayed sleep phase syndrome and headache did not differ significantly from that in the patients with the sleep disorder but without headache. Melatonin may be helpful in patients with headache who are suffering from delayed sleep phase syndrome. Its effectiveness may be due to modification of vascular and nociceptive systems or to its chronobiological action which adjusts the patient's biological clock to his/her life-style.

Adolescent↗
PubMed1996

Sequence of the 11 beta-hydroxylase gene from the Cape baboon (Papio ursinus).

We investigated the nucleotide sequence of the steroid 11 beta-hydroxylase gene (CYP11B1) from the Cape baboon (Papio ursinus). Six primers, previously used in studies on human CYP11B1, were utilised to amplify three overlapping fragments (A, B and C) of the baboon CYP11B1 by the polymerase chain reaction (PCR). Sequence analysis of the three fragments yielded the sequence of all the exons of baboon CYP11B1. The open reading frame of 1509 bases shows 57 nucleotide exchanges when compared to the human resulting in 18 amino acid substitutions. For eight of these exchanges we found the amino acid which is common for human aldosterone synthase at the corresponding position. Most of the remaining 10 amino acid substitutions were conservative. Eight of the substitutions were located in the first four exons with a cluster in the second half of exon 3. One substitution was in exon 5 (F280L) and the 10th was C494F at the end of the protein.

Animals↗
PubMed1993

Inhibition of cytochrome P-450(11)beta by some naturally occurring acetophenones and plant extracts from the shrub Salsola tuberculatiformis.

Ingestion of the Namibian shrub Salsola tuberculatiformis Botsch. by virgin female rats extends the dioestrus period of their oestrous cycles. Methanol extracts of the plant also inhibit adrenal steroidogenesis in the rat. With the aid of a bioassay, in which vaginal smears were used to follow the oestrous cycles of virgin rats, active fractions could be obtained which indicated that the plant contains a number of active compounds. The most active of these are highly unstable compounds which could not be isolated in pure form. However, two stable but less active compounds were identified as 4-hydroxyacetophenone and 4-hydroxy-3-methoxyacetophenone. This study investigated the influence of these acetophenones, their glucosides, and that of ethanol extracts of S. tuberculatiformis on adrenal steroidogenesis. Acetovanillon, a structurally related natural product also known as compound Z, was included in this study. Results show that the shrub contains active substances which interfere with adrenal 11 beta-hydroxylase, the terminal enzyme in glucocorticoid biosynthesis. This interaction with the cytochrome P-450(11)beta-dependent hydroxylase, as well as the inhibition of the conversion of deoxycorticosterone to corticosterone, was used to develop two sensitive and reliable assays for the rapid identification of small amounts of active compounds from S. tuberculatiformis.

Acetophenones↗
PubMed1993

Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase.

Progesterone and pregnenolone are metabolized to 17 alpha-hydroxysteroids by a cytochrome P450-dependent 17 alpha-hydroxylase (P450c17). The same enzyme can also catalyze the removal of the side-chain of these 17 alpha-hydroxylated steroids to yield androstenedione and dehydroepiandrosterone, respectively. We investigated the metabolism of progesterone by monkey kidney tumor (COS 1) cells transfected with a plasmid vector containing the cDNA encoding the complete amino acid sequence for human cytochrome P450c17. Transfected COS 1 cells converted progesterone to 17 alpha-hydroxyprogesterone as well as 16 alpha-hydroxyprogesterone, but no detectable androstenedione was produced. However, pregnenolone was converted to 17 alpha-hydroxypregnenolone and, ultimately, dehydroepiandrosterone. No 16 alpha-hydroxypregnenolone was produced. The kinetics of progesterone metabolism by the enzyme expressed in COS 1 cells indicated that both 17 alpha- and 16 alpha-hydroxylated products were products were produced from a common active site. Microsomes prepared from fetal adrenal and adult testis converted progesterone to 17 alpha-hydroxyprogesterone as well as 16 alpha-hydroxyprogesterone. No detectable androstenedione was produced by these preparations. Antibodies raised against porcine cytochrome P450c17 inhibited the 17 alpha- and 16 alpha-hydroxylation of progesterone to the same extent when using fetal adrenal microsomes, whereas no inhibition of 21-hydroxylation of progesterone was observed. Similar results were obtained with the imidazole antimycotic agent ketoconazole, which is a preferential cytochrome P450c17 inhibitor. From these results we conclude that human cytochrome P450c17 exhibits marked progesterone 16 alpha-hydroxylase activity in addition to its 17 alpha-hydroxylase function when expressed not only in a heterologous cell expression system but also, importantly, in human steroidogenic cells. Furthermore, the human enzyme has extremely low C-17,20-lyase activity toward progesterone, 17 alpha-hydroxyprogesterone, and 16 alpha-hydroxyprogesterone and fails to convert these to corresponding C19 steroids.

17-alpha-Hydroxyprogesterone↗
PubMed1985

A novel method for the preparation of substrate-free cytochrome P-450(11) beta.

A new method for the removal of the stabilizing substrate, deoxycorticosterone, from adrenal cytochrome P-450(11) beta, has been developed. Dextran coated charcoal is used for the adsorption of the steroid and the adsorbed steroid is separated from the cytochrome P-450-preparation by low speed centrifugation. The substrate-free enzyme, obtained in this manner, has all the characteristic spectral properties of low-spin cytochrome P-450(11) beta and may be converted to the high-spin form by the addition of deoxycorticosterone. The dextran coated charcoal method has the following advantages over the previously used method of substrate removal. It does not require the addition of the cofactors for cytochrome P-450-dependant hydroxylation of deoxycorticosterone, small amounts of enzyme may be prepared in a short time and the enzyme preparation is not diluted to any great extent during the process.

Adrenal Cortex↗
PubMed1977

Biologic activities of various thymus preparations.

Thymosin and THF were prepared from total normal calf thymus (TT), from calf thymus depleted of thymocytes by whole-body irradiation (TE), and from calf thymus lymphocytes (TL). The activities of these products were compared in four different in vitro assays that monitored for various T-cell functions. The results suggest that the preparations obtained from thymus epithelium are more active in inducing T helper cell function in nude/nude mouse spleen cells than substances isolated from thymus lymphocytes. The latter seem to act on a more advanced step in the T cell line differentiation.

Animals↗
PubMed1975

The nature of the polymeric serum IgA in man.

The nature and the amount of polymeric IgA in sera from normal, adult humans was investigated by means of three markers that selectively differentiate polymeric IgA: the capacity to bind secretory component; the presence of the J chain; and the reactivity with an antiserum that recognizes only the polymeric form of IgA. The results demonstrated that the sera of healthy adults contain only minimal amounts (less than 1% of the total serum IgA) of the true dimeric IgA. These conditions are valid for healthy individuals only. Pathological conditions at the secretory sites may result in increased values for the dimeric as well as for the secretory IgA in serum.

Adult↗