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Biomedical subjects

G S Marks

Publications and source records attributed to G S Marks.

At least 145 records · Page 8Linked to original sources
PubMed1982

Investigation of the membrane-fluidizing properties of porphyrin-inducing drugs.

The objective of this study was to test the hypothesis that porphyrin-inducing drugs act at least in part by disrupting membrane lipids. The porphyrin-inducing steroids, 3 alpha-hydroxy-5 alpha-pregnane-11,20-dione (alfaxalone) and 3 alpha-hydroxy-5 alpha-pregnan-20-one induce considerably greater fluidity changes in spin-labelled phospholipid-cholesterol bilayers than do the corresponding 3 beta-hydroxy steroids which are also less potent as porphyrin inducers. The steroids did not cause any significant change in spin-labelled vesicles lacking cholesterol. The porphyrin-inducing compound 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine and a series of analogues caused fluidity changes in phospholipid bilayers in the presence and absence of cholesterol. The porphyrin-inducing nonplanar 2,2',4,4'-6,6'-hexachlorobiphenyl caused a significant change in bilayer fluidity in phospholipid bilayers in the presence and absence of cholesterol. Since the planar 3,3',4,4'-tetrachlorobiphenyl, allylisopropylacetamide (AIA), and griseofulvin are potent porphyrin-inducing compounds, but do not fluidize a lipid bilayer, it was clear that the original hypothesis required modification. No evidence could be obtained to support the idea that a subset of porphyrin-inducing drugs exists which are membrane fluidizers and whose common mechanism of action as porphyrin-inducers might be revealed by a common pattern of porphyrin accumulation in chick embryo liver cells. It is suggested that those porphyrin-inducing compounds with membrane-fluidizing properties might fluidize the nuclear membrane, thus facilitating the transfer of an induction specific RNA for delta-aminolevulinic acid synthetase from the nucleus to the cytoplasm.

Allylisopropylacetamide↗
PubMed1982

Alterations in the heme biosynthetic pathway as an index of exposure to toxins.

Under normal circumstances the heme biosynthetic pathway is carefully controlled and porphyrins are formed in only trace amounts. When control mechanisms are disturbed by xenobiotics, porphyrins may be formed and serve as a signal of the interaction between a xenobiotic and the heme biosynthetic pathway. For example, porphyrinuria was an early manifestation of a hexachlorobenzene-induced porphyria outbreak in Turkey. In humans exposed to polybrominated biphenyls and to 2,3,7,8-tetrachlorodibenzo-p-dioxin the urinary porphyrin pattern was significantly different from normal in a large number of exposed individuals. The question is raised whether measurement of urinary porphyrin profiles by improved methods will enable an estimate to be made of the extent of exposure to haloaromatic hydrocarbons in the human population. A wide variety of xenobiotics interact with the prosthetic heme of cytochrome P-450 forming novel N-alkylporphyrins. Identification of these N-alkylporphyrins in body fluids might provide a means of assessing exposure to a variety of xenobiotics in human populations.

Cytochrome P-450 Enzyme System↗
PubMed1982

Investigations into the role of sulfhydryl groups in the mechanism of action of the nitrates.

The mechanism by which nitroglycerin (GTN) initiates relaxation in vascular smooth muscle is not known. According to one hypothesis a specific nitrate receptor exists with a key sulfhydryl (SH) group in the active site. The current study was performed with sulfhydryl reagents in helical strips of the canine medial saphenous vein from 20 dogs to examine the role of the SH group in the action of GTN. The reagents used were 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB) and p-chloromercuribenzoate (PCMB) which bind to and inactivate SH groups, and dithiothreitol (DTT), an SH reducing agent. It was anticipated that DTNB and PCMB would decrease the sensitivity to GTN while DTT might increase the sensitivity to GTN. Treatment of strips with PCMB and DTNB did not alter the dose-response curves for GTN. In contrast, following DTT treatment (1 x 10(-4)M) the maximum response to GTN (10(-5)M) was significantly reduced from 80.3% +/- 4.0 (SD) in control strips to 46.9% +/- 4.4 (SD) in the treated strips. These data suggest that relaxation induced by GTN in vascular smooth muscle occurs by a mechanism other than interaction with membrane SH groups.

Animals↗
PubMed1982

Arterial-venous nitroglycerin gradient during intravenous infusion in man.

We assessed the concentration of nitroglycerin (GTN) measured in plasma at different sampling sites in the circulation during a constant i.v. infusion. Twenty patients with chronic congestive cardiac failure underwent hemodynamic monitoring during i.v. GTN infusion. Our end point was a reduction in pulmonary capillary wedge pressure by at least 25% of its control value or a 10-fold increment over the initial infusion rate. Nitroglycerin infusion produced no change in heart rate, a reduction in mean arterial pressure from 90 +/- 21 (+/- SD) to 83 +/- 17 mm Hg (p less than 0.001), a fall in total peripheral resistance from 24.3 +/- 10.8 to 20.8 +/- 7.0 units (p less than 0.02), and a substantial reduction in both pulmonary capillary wedge pressure (from 27 +/- 6 to 20 +/- 6 mm Hg, p less than 0.001) and right atrial pressure (from 12 +/- 4 to 8 +/- 4 mm Hg, p less than 0.001). The concentrations of GTN in the pulmonary artery and systemic artery were similar (29.8 ng/ml +/- 52.8 and 25.1 +/- 48.4 ng/ml, respectively) and considerably higher than the concentration in the peripheral vein (7.3 +/- 15.4 ng/ml). There was a 17.4 +/- 19.1% extraction of GTN across the pulmonary vascular bed and a 60.8 +/- 27.2% extraction across the arterial-venous bed (p less than 0.001). There was no relationship between the arterial-venous extraction and the magnitude of arterial plasma (GTN concentration, the duration of the infusion of GTN or the total dose administered. These data show that a better understanding of GTN pharmacokinetics is provided by simultaneous arterial and venous samples.

Adult↗
PubMed1981

Effects of porphyrin-inducing drugs on ferrochelatase activity in isolated mouse hepatocytes.

The effects of several concentrations of griseofulvin and 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) on ferrochelatase activity in suspensions of isolated mouse hepatocytes were examined. In agreement with previous findings in the intact chick embryo liver and chick embryo liver cell culture, DDC, but not griseofulvin, inhibited the enzyme in the isolated mouse hepatocyte suspension. These results indicate that the difference between the effects of griseofulvin on hepatic ferrochelatase in rodents in vivo (inhibition), the intact chick embryo (no effect), and the chick embryo liver cell culture (no effect) cannot be attributed solely to species differences.

Animals↗
PubMed1980

Second derivative-high-performance liquid chromatographic-fluorometric detection of porphyrins in chick embryo liver cell culture medium.

A high-performance liquid chromatographic system is described which is suitable for the separation and quantitative determination of a mixture of porphyrin esters in nanogram quantities from the culture medium used for maintenance of a monolayer culture of chick embryo liver cells. The desired sensitivity was obtained by coupling a high-performance liquid chromatograph with a second derivative-fluorometric detection system. The most effective method for preparation of the porphyrin methyl esters prior to chromatography was found to be lyophilization of the culture medium prior to esterification with 5% sulphuric acid in methanol.

Animals↗
PubMed1980

Rapid disappearance of nitroglycerin following incubation with human blood.

Nitroglycerin (GTN) (at a concentration of 50 ng/mL) was incubated aerobically at 37 degrees C with whole blood, resuspended cells, and plasma from five normal volunteers. At several time periods following the initiation of the incubation (0, 1.5, 3, 5, 10, and 20 min for blood and resuspended cells, and 0, 30, 45, 60, 120, and 180 min for plasma) the samples were assayed for GTN in the incubation medium. Linear regression analyses were performed between the logarithm of the percentage GTN remaining and incubation time in order to determine the rate of disappearance of GTN from each system. A short t 1/2 for GTN was found in blood (6.2 min) and resuspended red cells (6.6 min) whereas a longer t 1/2 of 53.4 min was determined in plasma. These data indicate that the metabolism of GTN in human blood is rapid and predominantly localized in the cellular compartment of the blood. It is concluded that (a) the short circulatory t 1/1 of GTN following clinical administration is explained, at least in part, by rapid metabolism in blood and (b) it is necessary to rapidly centrifuge blood from GTN-treated patients and to freeze the plasma in order to prevent the breakdown of GTN prior to analysis.

Erythrocytes↗
PubMed1980

A comparison of the porphyrin-inducing activity of barbiturates and benzodiazepines in chick embryo liver cells.

Five benzodiazepines, flurazepam, nitrazepam, diazepam, oxazepam, and chlordiazepoxide, have been tested for porphyrin-inducing activity in chick embryo liver cell culture and for delta-aminolevulinic acid (ALA) synthetase inducing activity in the 17-day-old chick embryo. Flurazepam and nitrazepam were found to have considerably lower potency than secobarbital whereas diazepam, oxazepam, and chlordiazepoxide were less potent than phenobarbital in these test systems. The following conclusions were arrived at. (1) A hypnotic dose of flurazepam or nitrazepam would be less likely than a comparable dose of secobarbital to increase ALA synthetase activity in a patient with hereditary hepatic porphyria. (2) A sedative dose of diazepam, oxazepam, or chlordiazepoxide would be less likely than a comparable dose of phenobarbital to increase ALA synthetase activity in a patient with hereditary hepatic porphyria. (3) The benzodiazepines, although apparently less likely to precipitate an attack than barbiturates, should be used with great caution in porphyria patients.

5-Aminolevulinate Synthetase↗