| 1. |
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| 2. |
- Abelson, Klas, et al.
(author)
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Intravenously administered oxotremorine and atropine, in doses known to affect pain threshold, affect the intraspinal release of acetylcholine in rats
- 2002
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In: Pharmacology and Toxicology. - : Blackwell. - 0901-9928 .- 1600-0773. ; 90:4, s. 187-192
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Journal article (peer-reviewed)abstract
- Abstract:Both systemically and intrathecally administered cholinergic agonists produce antinociception while cholinergic antagonists decrease pain threshold. The mechanism and the site of action of these substances are not known. In the present study it was hypothesized that systemically administered muscarinic agonists and antagonists modify nociceptive threshold by affecting intraspinal release of acetylcholine (ACh). Catheters were inserted into the femoral vein in rats maintained on isoflurane anaesthesia for administration of oxotremorine (10–300 μg/kg) and atropine (0.1, 10, 5000 μg/kg). Spinal microdialysis probes were placed intraspinally at approximately the C2–C5 spinal level for sampling of acetylcholine and dialysis delivery of atropine (0.1, 1, 10 nM). Additionally, the tail-flick behaviour was tested on conscious rats injected intraperitoneally with saline, atropine (10, 100 and 5000 μg/kg), or subcutaneously with oxotremorine (30, 100, 300 μg/kg). Subcutaneous administration of oxotremorine (30, 100, 300 μg/kg) significantly increased the tail-flick latency. These doses of oxotremorine dose-dependently increased the intraspinal release of acetylcholine. Intravenously administered atropine, in a dose that produced hyperalgesia (5000 μg/kg) in the tail-flick test, significantly decreased the intraspinal release of acetylcholine. Our results suggest an association between pain threshold and acetylcholine release in spinal cord. It is also suggested that an approximately 30% increase in basal ACh release produces antinociception and that a 30% decrease in basal release produces hyperalgesia.
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| 3. |
- Abelson, Klas, et al.
(author)
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The effects of the alpha2-adrenergic receptor agonists clonidine and rilmenidine, and antagonists yohimbine and efaroxan, on the spinal cholinergic receptor system in the rat
- 2004
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In: Basic & Clinical Pharmacology & Toxicology. - : Blackwell. - 1742-7835 .- 1742-7843. ; 94:4, s. 153-60
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Journal article (peer-reviewed)abstract
- Cholinergic agonists produce spinal antinociception via mechanisms involving an increased release of intraspinalacetylcholine. The cholinergic receptor system interacts with several other receptor types, such as a2-adrenergic receptors.To fully understand these interactions, the effects of various receptor ligands on the cholinergic system must be investigatedin detail. This study was initiated to investigate the effects of the a2-adrenergic receptor agonists clonidine and rilmenidineand the a2-adrenergic receptor antagonists yohimbine and efaroxan on spinal cholinergic receptors in the rat. Spinalmicrodialysis was used to measure in vivo changes of acetylcholine after administration of the ligands, with or withoutnicotinic receptor blockade. In addition, in vitro binding properties of the ligands on muscarinic and nicotinic receptorswere investigated. It was found that clonidine and rilmenidine increased, while yohimbine decreased spinal acetylcholinerelease. Efaroxan affected acetylcholine release differently depending on concentration. Nicotinic receptor blockade atten-uated the effect of all ligands. All ligands showed poor binding affinity for muscarinic receptors. On the other hand, allligands possessed affinity for nicotinic receptors. Clonidine and yohimbine binding was best fit to a one site binding curveand rilmenidine and efaroxan to a two site binding curve. The present study demonstrates that the tested a2-adrenergicreceptor ligands affect intraspinal acetylcholine release in the rat evoked by nicotinic receptor mechanisms in vivo, andthat they possess binding affinity to nicotinic receptors in vitro. The binding of a2-adrenergic receptor ligands to nicotinicreceptors might affect the intraspinal release of acetylcholine.
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| 4. |
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| 5. |
- Barg, Sebastian
(author)
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Mechanisms of exocytosis in insulin-secreting B-cells and glucagon-secreting A-cells.
- 2003
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In: Pharmacology and Toxicology. - : Wiley. - 1600-0773 .- 0901-9928. ; 92:1, s. 3-13
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Research review (peer-reviewed)abstract
- In pancreatic B- and A-cells, metabolic stimuli regulate biochemical and electrical processes that culminate in Ca2+-influx and release of insulin or glucagon, respectively. Like in other (neuro)endocrine cells, Ca2+-influx triggers the rapid exocytosis of hormone-containing secretory granules. Only a small fraction of granules (<1% in insulin-secreting B-cells) can be released immediately, while the remainder requires translocation to the plasma membrane and further "priming" for release by several ATP- and Ca2+-dependent reactions. Such functional organization may account for systemic features such as the biphasic time course of glucose-stimulated insulin secretion. Since this release pattern is altered in type-2 diabetes mellitus, it is conceivable that disturbances in the exocytotic machinery underlie the disease. Here I will review recent data from our laboratory relevant for the understanding of these processes in insulin-secreting B-cells and glucagon-secreting A-cells and for the identification of novel targets for antidiabetic drug action. Two aspects are discussed in detail: 1) The importance of a tight interaction between L-type Ca2+-channels and the exocytotic machinery for efficient secretion; and 2) the role of intragranular acidification for the priming of secretory granules and its regulation by a granular 65-kDa sulfonylurea-binding protein.
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| 6. |
- Bergdahl, Andreas, et al.
(author)
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Lovastatin Induces Relaxation and Inhibits L-Type Ca2+ Current in the Rat Basilar Artery.
- 2003
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In: Pharmacology and Toxicology. - : Wiley. - 1600-0773 .- 0901-9928. ; 93:3, s. 128-134
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Journal article (peer-reviewed)abstract
- Statins inhibit cholesterol biosynthesis and protect against ischaemic stroke. It has become increasingly apparent that the beneficial effects of statin therapy may extend beyond lowering of serum cholesterol. The present study was done to explore possible pleiotropic statin effects at the level of the cerebral vascular smooth muscle. Lovastatin, lovastatin acid, simvastatin and pravastatin, were added to segments of the rat basilar artery and effects on contraction and Ca2+ handling were examined. Pravastatin had no effect on contraction. Simvastatin, lovastatin, and, to a lesser degree, lovastatin acid, caused relaxation (IC50=0.8, 1.9 and 22 μmol/l) of both intact and denuded arteries precontracted with 5-HT or high-K+. This effect was not reversed by mevalonate, suggesting that it was not related to cholesterol or isoprenoid metabolism. Relaxation was associated with a reduction of the intracellular Ca2+ concentration measured with Fura 2 and with a reduced Mn2+ quench rate, suggesting a direct effect on ion channels in the smooth muscle cell membrane. Current measurements in isolated and voltage clamped basilar artery muscle cells demonstrated that both lovastatin and lovastatin acid inhibit L-type Ca2+ current. We propose that lipophilicity is an important factor behind the effects of statins on vascular tone and that Ca2+ current inhibition is the likely mechanism of action.
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| 7. |
- Carlsson, Carina, et al.
(author)
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2,6-Dichlorophenyl methylsulphone induced behavioural impairments in rats and mice in relation to olfactory mucosal metaplasia
- 2003
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In: Pharmacology and Toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 93:4, s. 156-168
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Journal article (peer-reviewed)abstract
- 2,6-Dichlorophenyl methylsulphone (2,6-diClPh-MeSO2) induces persistent olfactory mucosal metaplasia and a strong glial fibrillary acidic protein increase in the olfactory bulb of mice. Furthermore, 2,6-diClPh-MeSO2 gives rise to a long-lasting hyperactivity along with an impaired radial arm maze performance. To study cause-effect relationships, olfactory mucosal histopathology, glial fibrillary acidic protein induction and neurobehavioural deficits were re-examined in mice and rats of both sexes given a single intraperitoneal dose of 2,6-diClPh-MeSO2 (16 and 65 mg/kg). There was a clear difference in the character of the olfactory mucosal lesions in the two species. In mice, an extensive metaplasia characterised by severe fibrosis, cartilage and bone formation accompanied with large polyps filling the nasal lumen was confirmed. In rats, a dose-dependent weak metaplasia with patchy loss of olfactory epithelium was observed three weeks after dosing, preferentially at the dorsal meatus, nasal septum, and the tips of the middle ethmoturbinates. Large areas of intact olfactory epithelium remained in all animals, particularly in the low dose rats. In both species, 2,6-diClPh-MeSO2 gave rise to significantly increased motor-activities, impaired performance in the radial arm maze, and glial fibrillary acidic protein-induction. Only rats showed hyperactivity at the low dose. Performance in the Morris water maze was unaffected in rats of both sexes indicating that a general impairment in spatial learning could not be supported. We propose that the observed hyperactivity and radial arm maze acquisition deficits originated from a direct effect of 2,6-diClPh-MeSO2 in the brain rather than being a consequence of the olfactory mucosal lesion.
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| 8. |
- Chen, D, et al.
(author)
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Gastric phenotypic abnormality in cholecystokinin 2 receptor null mice
- 2002
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In: Pharmacology and Toxicology. - : Wiley. - 1600-0773 .- 0901-9928. ; 91:6, s. 375-381
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Journal article (peer-reviewed)abstract
- Gastrin, released from antral G-cells, plays an important role in the regulation of gastric acid secretion and is trophic for the stomach, The cholecystokinin type 2 (CCK)(2) receptor (previously referred to as CCK-B/gastrin receptors) is expressed in both parietal cells and ECL cells in the oxyntic mucosa of stomach. Gastric phenotypic abnormality has been observed in CCK2 receptor null (gene knock-out) mice. Such mice displayed markedly impaired gastric acid secretion, atrophy of the oxyntic mucosa and hypergastrinaemia. The impaired acid secretion may be the result of a reduced parietal cell mass, a reduced proportion of actively secreting parietal cells (with secretory canaliculi), and a replacement of ECL cells by histamine-free ECL-like cells. The ECL-like cells, observed in the CCK2 receptor null mice, lacked the hallmark features of wild-type ECL cells, i.e. histamine and cytoplasmic secretory vesicles. However, they had the features of endocrine cells, such as the content of pancreastatin (a fragment of chromogranin A), with cytoplasmic small dense-core granules and microvesicles. We propose that the replacement of ECL cells by ECL-like cells in the mutant mice reflects an altered differentiation of the same precursors that develop into ECL cells in wild-type mice. Thus, studies of CCK2 receptor null mice demonstrate the importance of the receptor in the regulation of gastric acid secretion and in the differentiation of ECL cells in the oxyntic mucosa of stomach.
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| 9. |
- Ericsson, Peter, et al.
(author)
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ECL Cell Histamine Mobilization Studied byGastric Submucosal Microdialysis in Awake Rats:Methodological Considerations.
- 2003
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In: Pharmacology and Toxicology. - : Wiley. - 1600-0773 .- 0901-9928. ; 93:2, s. 57-65
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Journal article (peer-reviewed)abstract
- The ECL cells are endocrine/paracrine cells in the acid-producing part of the stomach. They secrete histamine in response to circulating gastrin. Gastric submucosal microdialysis has been used to study ECL-cell histamine mobilization in awake rats. In the present study we assess the usefulness and limitations of the technique. Microdialysis probes were implanted in the gastric submucosa. Histological analysis of the stomach wall around the probe revealed a moderate, local inflammatory reaction 1-2 days after implantation; the inflammation persisted for at least 10 days. Experiments were conducted 3 days after the implantation. The "true" submucosal histamine concentration was determined by perfusing at different rates (the zero flow method) or with different concentrations of histamine at a constant rate (the no-net-flux method): in fasted rats it was calculated to be 87±5 (means±S.E.M.) nmol/l and 76±9 nmol/l, respectively. The corresponding histamine concentrations in fed rats were 93±5 and 102±8 nmol/l, respectively. With a perfusion rate of 74 mul/hr the recovery of submucosal histamine was 49%, at 34 mul/hr the recovery increased to 83%. At a perfusion rate below 20 mul/hr the microdialysate histamine concentration was close to the actual concentration in the submucosa. The ECL-cell histamine mobilization was independent of the concentrations of Ca2+ in the perfusion medium (0-3.4 mmol/l Ca2+). In one experiment, histamine mobilization in response to gastrin (10 nmol/kg/hr subcutaneously) was monitored in rats pretreated with prednisolone (60 mg/kg) or indomethacin (15 mg/kg). The two antiinflammatory agents failed to affect the concentration of histamine in the microdialysate either before or during the gastrin challenge, which was in accord with the observation that the inflammatory reaction was modest and that inflammatory cells were relatively few around the probe and in the wall of the probe. In another experiment, rats were given aminoguanidine (10 mg/kg) or metoprine (10 mg/kg) 4 hr before the start of gastrin infusion (5 nmol/kg/hr intravenously). Metoprine (inhibitor of histamine N-methyl transferase) did not affect the microdialysate histamine concentration, while aminoguanidine (inhibitor of diamine oxidase) raised both basal and gastrin-stimulated histamine concentrations. We conclude that microdialysis can be used to monitor changes in the concentration of histamine in the submucosa of the stomach, and that the inflammatory reaction to the probe is moderate and does not affect the submucosal histamine mobilization.
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| 10. |
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| 11. |
- Green, Henrik, et al.
(author)
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Spontaneous Reversal of P-Glycoprotein Expression in Multidrug Resistant Cell Lines
- 2003
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In: Pharmacology and Toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 93:6, s. 297-304
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Journal article (peer-reviewed)abstract
- Increased expression of P-glycoprotein encoded by the mdr-1 gene is a well-characterised mechanism for resistance to cancer chemotherapeutic drugs in cell lines. However, the P-glycoprotein expression after removal of the selection pressure has not fully been elucidated. The stability of P-glycoprotein expression in the presence (+) and absence (-) of vincristine (30 or 150 nM) was studied in multidrug resistant K562 cell lines (VCR30+, VCR150+, VCR30- and VCR150-) for 11 months. The P-glycoprotein protein and mdr-1 mRNA levels were determined at regular intervals using flow cytometry and real-time PCR, respectively. Chemosensitivity to a panel of antineoplastic drugs was measured using an MTT assay. The presence of vincristine (VCR30+ and VCR150+) resulted in high and stable levels of P-glycoprotein and mdr-1 mRNA during the whole period compared to wild type. As for the VCR30- and VCR150- subcultures, the expressions of P-glycoprotein and mdr-1 mRNA were stable for five months, and then the levels decreased rapidly. Concomitantly, the sensitivity to drugs known as P-glycoprotein substrates was restored. In conclusion, resistant cells growing in the presence of the inducing drug have a stable P-glycoprotein expression and resistance level, but removing the inducing drug may result in a sudden and rapid lowering of P-glycoprotein and mdr-1 mRNA levels as long as five months after drug withdrawal.
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| 12. |
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| 13. |
- Hakansson, H, et al.
(author)
-
In memoriam - Ulf G. Ahlborg
- 2002
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In: PHARMACOLOGY & TOXICOLOGY. - : Wiley. - 0901-9928. ; 91:5, s. 218-219
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Journal article (other academic/artistic)
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| 14. |
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| 15. |
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| 16. |
- Kotarsky, Knut, et al.
(author)
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Progress in methodology improved reporter gene assays used to identify ligands acting on orphan seven-transmembrane receptors.
- 2003
-
In: Pharmacology and Toxicology. - : Wiley. - 1600-0773 .- 0901-9928. ; 93:6, s. 249-258
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Research review (peer-reviewed)abstract
- Seven-transmembrane G-protein-coupled receptors play a central role in physiology by facilitating cell communication through recognition of a wide range of ligands. Even more important, they represent important drug targets. Unfortunately, for many of these receptors the endogenous ligands, and hence their functions, remain to be identified. These receptors are referred to as "orphan" receptors. A pre-requisite for the identification of ligands activating orphan receptors is powerful assay systems. Until now, reporter gene assays have not been in common use in this process. Here, we summarize our development of improved reporter gene assays. We optimized reporter gene assays in respect of (i) the promoter region of the construct, (ii) the reporter enzyme used, (iii) and the assay procedure. Furthermore, an unique fluorescence-based clone selection step was introduced, allowing rapid selection of the most sensitive reporter cell clones when establishing stable reporter cell lines. Mathematical formulae are provided to enable a simple and reliable comparison between different cell lines, when tested with a compound of interest. The resulting reporter cell lines responded in a very sensitive way to the stimulation of various test receptors. The reporter system was termed HighTRACE® (high-throughput reporter assay with clone election). Its high assay quality makes it suitable as a primary screening tool. Ligands for two recently unknown 7TM receptors were identified using the HighTRACE® system i.e., two cell surface free fatty acid receptors, GPR40 (FFA1R) and GPR43 (FFA2R). The identification was accomplished using a reverse pharmacology approach.
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| 17. |
- Kugelberg, Fredrik C., et al.
(author)
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Effects of chronic citalopram treatment on central and peripheral spontaneous open-field behaviours in rats
- 2002
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In: Pharmacology and Toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 90:6, s. 303-310
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Journal article (peer-reviewed)abstract
- The spontaneous open-field behavioural effects of 10 days of chronic treatment with two clinical doses (10 and 20 mg/kg daily) and one high/toxic dose (100 mg/kg daily) of the selective serotonin reuptake inhibitor citalopram (delivered subcutaneously by implanted osmotic pumps) were examined in rats. Central and peripheral arena locomotor and rearing activities were recorded simultaneously, and the data were assessed during the first hour as well as during the following 24 hr (the latter for effects on the diurnal rhythm). Rats treated with 100 mg/kg daily exhibited lower peripheral locomotor and rearing activities than the other groups during the first test hour. The ratio between central and peripheral activity increased in a dose-dependent non-proportional manner during the first test hour, indicating a general increase in the central arena activity exerted by the rats when treated with citalopram. No major differences were observed between any of the four groups in overall behavioural activities over the 24-hr period. This study indicated that the open-field locomotor and rearing behaviours in normal rats were affected by increasing doses of racemic citalopram, particularly during the first hour of adaptation.
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| 18. |
- Källén, Bengt
(author)
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Valproic Acid is Known to Cause Hypospadias in Man but does not Reduce Anogenital Distance or Causes Hypospadias in Rats.
- 2004
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In: Pharmacology and Toxicology. - : Wiley. - 1600-0773 .- 0901-9928. ; 94:1, s. 51-54
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Journal article (peer-reviewed)abstract
- The use of valproic acid during human pregnancy increases the risk of hypospadias in the offspring. Rats exposed in utero to valproic acid did not develop hypospadias and even had a slightly increased anogenital distance in males 3-4 days after birth. A classical antiandrogenic drug, flutamide, caused hypospadias as well as a reduction of the anogenital distance in males. At the age of 3 months, rats exposed in utero with either valproic acid or flutamide showed a reduced testicular weight and hypoplasia of tubules, which seemed not to be related to the antiandrogenic activity of flutamide as it did not correlate with the presence of hypospadias. The mechanism through which valproic acid causes hypospadias in man and affects testicular development in rat is unknown. Hypospadias caused by valproic acid in man is apparently not due to anti-androgenic properties of the drug.
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| 19. |
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| 20. |
- Lind, Anna-Britta, et al.
(author)
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Gene expression of cytochrome P450 1B1 and 2D6 in leukocytes in human pregnancy
- 2003
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In: Pharmacology and Toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 92:6, s. 295-9
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Journal article (peer-reviewed)abstract
- We investigated the influence of human pregnancy on gene expression of two cytochrome P450 enzymes in white blood cells. Cytochrome P450 1B1 (CYP1B1) catalyses oestradiol 4-hydroxylation, and may participate in the endocrine regulation of oestrogens. Cytochrome P450 2D6 (CYP2D6) metabolises many commonly used drugs, and previous studies have suggested that it is induced during pregnancy. CYP1B1 and CYP2D6 were therefore considered to be of interest in human pregnancy. As it is not ethically possible to take liver biopsies from healthy mothers during pregnancy, easily accessible cells that express the genes were used as a surrogate tissue. White blood cells were collected from eighteen pregnant women, and were used to measure CYP1B1 and CYP2D6 ribonucleic acid (RNA). The analysis was repeated after pregnancy, the women, thus, serving as their own controls. Real-time reverse transcriptase - polymerase chain reaction methods were used with 18S ribosomal RNA as an internal control. A slight, but not significant, increase in gene activity of CYP1B1 was detected during pregnancy. Expression of CYP2D6 in blood was extremely low, and induction of CYP2D6 during pregnancy could not be confirmed. In conclusion, gene expression of CYP1B1 and CYP2D6 in leukocytes was not significantly up-regulated in the third trimester of pregnancy, but a trend indicating an altered metabolism during pregnancy was detected.
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| 21. |
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| 22. |
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| 23. |
- Naidu Sjöswärd, Kerstin, 1938-, et al.
(author)
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Metabolism of salbutamol differs between asthmatic patients and healthy volunteers
- 2003
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In: Pharmacology and Toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 92:1, s. 27-32
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Journal article (peer-reviewed)abstract
- Patients with asthma are a target group for medication with β2-agonists, often in combination with corticosteroids. Salbutamol is commonly marketed as racemate. R-Salbutamol carries β2-agonistic property whereas S-salbutamol does not. The racemate undergoes stereoselective sulphatisation by sulfotransferases mainly in the gut and liver, so that S-salbutamol rests for a longer time in the body and reaches higher plasma levels than R-salbutamol. Ten patients with mild stable asthma and at present without cortisone medication were given racemic salbutamol as ventoline 4 mg orally. Plasma and urine levels were estimated until 24 hr after ingestion. For comparison healthy volunteers were treated in the same way.The group of asthma patients was then treated with budesonide inhalations 800 μg daily for one week and the initial programme resumed. Non-cortisone-treated asthmatic patients displayed higher levels of both R- and S-salbutamol in plasma than did healthy volunteers after one single ingestion of racemic salbutamol (CMAX both comparisons P<0.05). Plasma levels of salbutamol isomers in cortisone-treated asthmatic patients resembled the levels in volunteers. The most plausible explanation for the discrepancy in values between asthmatic patients and volunteers is a defective metabolic function by asthmatic patients possibly enzymatic in origin.
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| 24. |
- Oberg, M, et al.
(author)
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Subchronic toxicity of Baltic herring oil and its fractions in the rat I: Fractionation and levels of organohalogen pollutants
- 2002
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In: Pharmacology and Toxicology. - : Wiley. - 1600-0773 .- 0901-9928. ; 91:5, s. 220-231
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Journal article (peer-reviewed)abstract
- Baltic herring (Clupea harengus) oil was extracted and fractionated. To examine the contribution to toxicity and biological effects of different halogenated organic pollutants, the herring oil and the fractions were mixed into pelleted food and given to Sprague-Dawley female rats at three levels, corresponding to a human intake of 1.6, 8.2 and 34.4 kg fish per week. Herring oil, its fractions, as well as liver tissues from exposed rats, were analyzed for: eight chlorinated biphenyls, all 2,3,7,8-substituted chlorinated dibenzo-p-dioxins and dibenzofurans, hexachlorocyclohexanes, hexachlorobenzene, 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (DDT), DDT-metabolites, three brominated diphenylethers as well as extractable organically bound chlorine and halogenated fatty acids. A bioassay (EROD) was used for measuring the dioxin-like enzyme induction activity. Nordic Sea lodda (Mallotus villosus) oil was used as a nutritionally equivalent control, with much lower levels of halogenated organic pollutants. A full toxicological subchronic examination is reported in the following paper (Stern et al. 2002). In this study, we report that the fractionation procedure resulted in a substantial reduction of most of the pollutants in the triacylglycerol fraction, and a pronounced enrichment of most of the pollutants into the two other fractions. However, all contaminants were present at some levels in all of the fractions. The concentrations of organoltalogens found in this study were representative for Baltic herring during the mid-1990s. Rat liver tissue showed similar residue patterns as the diet, with the exception of chlorinated dibenzo-p-dioxin and dibenzofuran congeners that had a higher liver retention than pesticides, chlorinated biphenyls and brominated diphenylethers.
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| 25. |
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| 26. |
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| 27. |
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| 28. |
- Stark, Katarina, et al.
(author)
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Expression of CYP4F12 in gastrointestinal and urogenital epithelia
- 2004
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In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 94:4, s. 177-83
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Journal article (other academic/artistic)abstract
- Cytochrome P450 4F12 (CYP4F12) was originally cloned from human liver and small intestine. CYP4F12 can oxidize arachidonic acid, two stable prostaglandin H2 analogues, and an antihistamine, ebastine, but the tissue distribution and catalytic properties of CYP4F12 have not been fully investigated. An antipeptide polyclonal antibody was raised against the C-terminal of CYP4F12 (PLNVGLQ), evaluated by Western blot analysis and used for immunohistological analysis of 50 human tissues. Western blot analysis of recombinant CYP4F12, expressed in yeast, and microsomal proteins from adult and foetal liver, kidney, placenta at term, seminal vesicles, the prostate gland and purified prostasomes showed that the polyclonal antibody detected a protein of the expected size, approximately 60 kDa. CYP4F12 mRNA could be detected in seminal vesicles and prostate gland by reverse transcription-PCR. Prominent CYP4F12 immunoreactivity occurred, inter alia, in the epithelial cells of the gastrointestinal tract (stomach, small intestine, and colon), collecting tubules, transitional epithelium, ovarian follicles, the endothelium of microvessels of placental villi (first trimester), and epidermis. We screened recombinant CYP4F12 for catalytic activity. Arachidonic acid (20:4n-6) was hydroxylated at C18 and laurate at C11, but significant amounts of metabolites of 18:2n-6, 20:3n-9, 20:5n-3, 22:5n-6, and some prostaglandins could not be detected. We conclude that CYP4F12 is widely distributed in gastrointestinal and urogenital epithelia and exhibits a narrow substrate specificity.
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| 29. |
- Stern, Natalia, et al.
(author)
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Subchronic toxicity of Baltic herring oil and its fractions in the rat II : Clinical observations and toxicological parameters.
- 2002
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In: Pharmacology and Toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 91:5, s. 232-244
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Journal article (peer-reviewed)abstract
- This study aimed to increase the knowledge about the toxicity of fish-derived organohalogen pollutants in mammals. The strategy chosen was to separate organohalogen pollutants derived from Baltic herring (Clupea harengus) fillet, in order to obtain fractions with differing proportions of identified and unidentified halogenated pollutants, and to perform a subchronic toxicity study in rats, essentially according to the OECD guidelines, at three dose levels. Nordic Sea lodda (Mallotus villosus) oil, with low levels of persistent organohalogen pollutants, was used as an additional control diet. The toxicological examination showed that exposure to Baltic herring oil and its fractions at dose levels corresponding to a human intake in the range of 1.6 to 34.4 kg Baltic herring per week resulted in minimal effects. The spectrum of effects was similar to that, which is observed after low-level exposure to pollutants such as chlorinated dibenzo-p-dioxins and dibenzofurans (CDD/F) and chlorinated biphenyls, despite the fact that these contaminants contribute to a minor part of the extractable organically bound chlorine (EOCl). The study confirmed previous findings that induction of hepatic ethoxyresorufin deethylase (EROD) activity takes place at daily intake levels 0.15 ng fish-derived CDD/F-TEQs/kg body weight. The study also demonstrated that hepatic vitamin A reduction takes place at somewhat higher daily exposure levels, i.e. 0.16–0.30 ng fish-derived CDD/F-TEQs/kg body weight. Halogenated fatty acids, the major component of EOCl, could not be linked to any of the measured effects. From a risk management point of view, the study provides important new information of effect levels for Ah-receptor mediated responses following low level exposure to organohalogen compounds from a matrix relevant for human exposure.
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| 30. |
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| 31. |
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| 32. |
- Waldeck, Bertil
(author)
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Three-dimensional pharmacology, a subject ranging from ignorance to overstatements.
- 2003
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In: Pharmacology and Toxicology. - : Wiley. - 1600-0773 .- 0901-9928. ; 93:5, s. 203-210
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Research review (peer-reviewed)abstract
- Stereoselectivity has been known to play a role in drug action for 100 years or more. Nevertheless, chiral drugs have been developed and used as racemates, neglecting the fact that they comprise mixtures of two or more compounds which may have quite different pharmacological properties. A very limited access to pure enantiomers in the past has been responsible for this unsatisfactory state of affairs. During the last 20 years, significant achievements have made it possible to perform stereoselective synthesis and analysis. Today, novel chiral drugs are as a rule developed as single enantiomers. Yet, studies of old racaemic drugs are still designed, performed and published without mention of the fact that two or more compounds are involved. In recent years, a number of old racaemic drugs have been re-evaluated and re-introduced into the clinical area as the pure, active enantiomer (the eutomer). While in principle correct, the clinical benefit of this shift from a well established racaemate to a pure enantiomer often seems to be limited and sometimes exaggerated. Racaemic drugs with a deleterious enantiomer that does not contribute to the therapeutic effect (the distomer), may have been sorted out in the safety evaluation process. However, in the future any pharmacological study of racaemic drugs must include the pure enantiomers. This will generate new, valuable information on stereoselectivity in drug action and interaction
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| 33. |
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