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Biomedical subjects

M W Anderson

Publications and source records attributed to M W Anderson.

At least 163 records · Page 9Linked to original sources
PubMed1979

Studies on the covalent binding of an intermediate(s) in prostaglandin biosynthesis to tissue macromolecules.

We investigated the covalent binding of intermediates in prostaglandin biosynthesis to tissue macromolecules. Following incubation of [1-14C]arachidonic acid with the microsomal fraction from guinea pig lung, ram or bovine seminal vesicle, human platelets, rabbit kidney, or rat stomach fundus, the amount of covalent binding of arachidonic acid metabolites expressed as percentage of total arachidonic acid metabolized varied from tissue to tissue ranging from 3% in human platelets to 18.2% in ram seminal vesicles. In general, the thromboxane synthesizing tissues had less covalently bound metabolites than the other tissues. The amount of covalently bound metabolites was increased in the guinea pig lung microsomes when the thromboxane synthetase inhibitor, N-0164, was added to the incubation mixture. The covalent binding of arachidonic acid metabolite(s) was greatly reduced by the addition of glutathione to the incubation mixture. In addition to the covalently bound metabolites, water-soluble metabolites derived from arachidonic acid metabolism were also observed. The amount of water-soluble metabolites was small in each tissue except for the rat stomach fundus. In the rat stomach fundus the water-soluble metabolites accounted for over 50% of the total metabolites. Conditions which would tend to increase or decrease the levels of free prostaglandin endoperoxides during the incubation of arachidonic acid with the microsomes gave increased or decreased levels of covalent binding. Our data suggest that the prostaglandin endoperoxides are responsible for the covalent binding observed during prostaglandin biosynthesis. This covalent binding to tissue macromolecules may be of physiological and pathological significance.

Animals↗
PubMed1979

Linkage analysis and the inheritance of arches in a Habbanite isolate.

A pedigree and linkage analysis was performed on a corrected version of the Habbanite pedigree 2 of Slatis et al. [1]. The trait "arch on any digit" was examined for major gene inheritance and possible linkage to several blood and serum group markers. The results confirm the proposed dominant major gene inheritance of this trait with almost complete penetrance. In addition, the analysis suggests linkage with the haptoglobin locus with evidence against linkage with Pl and Rhesus. These results are of particular interest in view of recently reported dermatoglyphic associations with haptoglobin.

Consanguinity↗
PubMed1978

Conjugation of 15-keto-prostaglandins by glutathione S-transferases.

Incubation of 15-keto[3H]prostaglandin F2alpha with glutathione (GSH) produced a metabolite of 15-keto-prostaglandin F2alpha which was not extractable from aqueous solution and thus termed 'water-soluble metabolite'. The addition of cytosol of guinea pig liver to the incubation mixture increased the formation of water soluble metabolite of 15-keto-prostaglandin F2alpha 3-fold. The conversion of 15-keto-prostaglandin F2alpha to water soluble metabolite in both the presence and absence of enzyme was linear during 10 min of incubation and required 2.5 mM GSH for maximal activity. Liver and kidney cytosol possess about 70 and 25 times, respectively, as much activity as compared to lung cytosol. Chromatographic analysis of the water soluble metabolite obtained from incubation of either 15-keto[3H]prostaglandin F2alpha and GSH or [3H]GSH and 15-keto-prostaglandin F2alpha showed that the water-soluble metabolite was an adduct of 15-keto-prostaglandin F2alpha and GSH. The addition of prostaglandin A1, a substrate of GSH S-transferases, to the incubation mixture competitively inhibited the formation of the water-soluble metabolite of 15-keto[3H]prostaglandin F2alpha. Presumably, 15-keto-prostaglandin F2alpha and other 15-keto-prostaglandins are converted to GSH conjugates by GSH S-transferases. This indicates that 15-keto-metabolites produced by prostaglandin dehydrogenase may be further metabolized to GSH conjugates.

Animals↗
PubMed1978

Kinetic studies on the conversion of prostaglandin endoperoxide PGH2 by thromboxane synthase.

We have investigated the time course of formation of thromboxane A2, thromboxane B2, and the C-17 hydroxy fatty acid, HHT, from arachidonic acid in a washed human platelet suspension. Our results indicate that HHT is not a breakdown product of thromboxane A2, but rather thromboxane A2 decomposes exclusively into thromboxane B2. The kinetics of formation of thromboxane B2 from the endoperoxide prostaglandin H2 in human platelet microsomes was examined. Our data suggest that a bimolecular reaction is involved in the formation of thromboxane A2 from prostaglandin H2 and that thromboxane synthase is not an isomerase, but may be acting via a dismutase-type reaction. One possibility is that thromboxane and HHT are produced simultaneously from two molecules of prostaglandin H2.

Arachidonic Acids↗
PubMed1977

The construction of a pharmacokinetic model for the disposition of polychlorinated biphenyls in the rat.

The construction of a preliminary pharmacokinetic model for the distribution, long-term storage sites, excretion, and metabolism of selected polychlorinated biphenyls (PCBs) in the rat is described. Following intravenous administration of radioactive PCBs, several metaboiltes of each PCB isomer were detected in urine or feces, excreted primarily as glucuronide conjugates. The relative and absolute amount of metabolites excreted depended upon the degree of chlorination and the position of the chlorine on the biphenyl molecule. Concerning long-term storage sties, an unanticipated finding was accumulation in skin, as revealed by the particularly long half-life of the 6-CB isomer in skin. A flow diagram of the model is presented, as are the differential equations, solved by computer for a given dose schedule, for the individual mass balances on parent and metabolite in each of the compartments that represent the organs or regions in which the concentration is assumed to be uniform. Low-level, long-term doses of PCBs produce a variety of toxicologic symptoms which appear only after long-time exposure. Such models should be useful in explaining and predicting the toxicities induced by exposure to PCBs and similar contaminants and the time required to reach a steady-state tissue concentration for given long-term doses.

Animals↗
PubMed1977

Structural requirements for, and the effects of chemicals on, the rat pulmonary inactivation of prostaglandins.

We have investigated the removal of prostaglandins (PGs) from the pulmonary circulation using the isolated perfused rat lung in order to determine which parts of the PG molecule were essential for transport into the pulmonary tissue. From these studies we propse that three functional groups of the PG molecule are necessary for transport into the lung tissue: the carboxylic acid group at carbon 1, hydroxyl group at carbon 15, and an oxygen group at carbon 11. The geometrical relationship between these groups is important for transport since reduction of the 13, 14-double bond reduced transport, and changing the C-15 hydroxyl from an S to R configuration abolished transport. Various chemicals, drugs, and PG antagonists were tested for their ability to inhibit the transport system resposible for PG removal from the circulation. Diphloretin phosphate and polyphloretin phosphate were effective inhibitors, whereas dexamethasone, bromocresol green N-ethyl maleimide and imipramine were moderately effective inhibitors. The PG antagonist, SC-19220, 7-oxo-13-prostynoic acid, and hydrocortisone were ineffective.

Animals↗
PubMed1977

Uptake and metabolism of prostaglandins by isolated perfused lung: species comparisons and the role of plasma protein binding.

We have investigated the uptake and subsequent metabolism of the prostaglandins (PGs) PGE1, PGA1, and PGB1 by rat, guinea pig and rabbit isolated perfused lungs (IPL). Significant species differences were not observed in the uptake or metabolism of any PG on passage through the IPL. However, differences in the uptake of PGA1 and PGB1 and in the metabolism of PGA1 were observed with a given species when the composition of the perfusion medium was varied. The IPL removed minimal amounts (less than 20% of the supply rate) of PGA1, and PGB1 from the circulation when the perfusate contained 4.5% bovine serum albumin (BSA). In the absence of BSA, however, both PGA1 and PGB1 were substantially removed from circulation (approximately 53% of the supply rate) and PGA1 was also metabolized. The composition of the perfusate had no effect on the uptake and metabolism of PGE1 which was always taken up and metabolized to a greater extent than was PGA1 and PGB1. Thus, the apparent species differences previously reported for the pulmonary biotransformation of PGA can result from differences in the perfusion medium used. Our data suggest that both plasma protein binding and a transport system play important roles in determining the selectively of the uptake of PGs by the lung.

Animals↗
PubMed1977

Pharmacokinetic models for lipophilic compounds.

In many instances pharmacokinetic modeling offers the best method of interpreting the significance to man of results obtained with laboratory animals but first we must have accurate models for our laboratory animals. A physiological pharmacokinetic model has been used to simulate the disposition of polychlorinated biphenyls (PCBs) in the rat and to extrapolate results obtained with the rat to predict the disposition of PCBs in the mouse. The modeling methods have also been extended to predict the disposition of a polybrominated biphenyl (PBB) in the rat following IV, oral, and multiple oral doses. It is anticipated that with additional experience and work a physiological pharmacokinetic model can be used to predict the disposition of these and other xenobiotics in man.

Animals↗
PubMed1976

Prostaglandin removal and metabolism by isolated perfused rat lung.

We have investigated the mechanism(s) involved in the removal of prostaglandins (PG) from the pulmonary circulation by the lung. Unidirectional fluxes of PG from the circulation into the lung are measured in an isolated perfused rat lung preparation. Evidence is presented which suggests that a transport system for PG exists in lung tissue. This transport system is responsible for the removal of some PG from the circulation by the lung. PGE1 and PGF2alpha are substrates for this system, whereas PGB1, PGA1, and 15-keto-PGF2alpha are not. Since PGA1 is a substrate for the intracellular PG dehydrogenase, the selectivity of the lung's metabolism system for circulating PG is probably due to the selectivity of the transport system for PG. It is shown that the percentage of the pulmonary arterial concentration (CA) of PGE1 or PGF2alpha that is metabolized on passage through the pulmonary circulation decreases rapidly as CA increases. When the lungs were perfused with PGE1(PGF2alpha), the metabolites detected in the venous effluent were 15-keto-PGE1 (PGF2alpha) and 15-keto-13, 14-dihydro-PGE1 (PGF2alpha). The time course pattern of the appearance of metabolites in the venous effluent after the initiation of a constant CA, and the relative concentrations of the metabolites in the venous effluent, were examined as a function of CA.

Animals↗
PubMed1976

Uptake, metabolism and efflux of methadone in "single pass" isolated perfused rabbit lungs.

The uptake, metabolism and persistence of racemic, d- and l-methadone were studied in the isolated perfused rabbit lung. The removal of the drug from the perfusate was resolved into two uptake processes (I1 and I2Y. The unidirectional flux of methadone from the perfusate into the lung was linear with respect to perfusate concentration, suggesting an uptake mechanism involving diffusion and/or binding. The uptake of d- and l-methadone was identical. In the absence of methadone in the perfusate, methadone that previously had accumulated in the lung effluxed at three rates (T1/2 = 0.37, 1.65 and 8.9 minutes) suggesting that accumulated methadone was stored in at least three pools (E1, E2, and E3) In addition, a pool with a half-life in excess of 5 hours (noneffuxable pool) was detected; this noneffluxable pool was shown not to be the result of irreversible covalent binding. Methadone was biotransformed to a small extent by the isolated perfused lung to mono- and di-N-demethylated metabolites. Although unchanged methadone and its N-demethylated metabolites were consistently found in the lung at the end of efflux, the mono-N-demethylated metabolite was not always detectable in the perfusate. Nevertheless, the decrease in the rate of efflux of the metabolites with respect to time was identical to that of unchanged methadone.

Animals↗
PubMed1975

The pharmacodynamics of 5-hydroxytryptamine uptake and metabolism by the isolated perfused rabbit lung.

We have investigated the dynamics for the removal of 5-hydroxytryptamine (5-HT) from the circulation using the isolated perfused rabbit lung. 5-HT was removed from the circulation at a constant rate and metabolized completely to 5-hydroxyindoleacetic acid which effluxed from the lung into the circulation. Two methods were developed to determine the constant rate of removal of 5-HT: (1) the constant rate is equal to the difference between the 5-HT concentration flowing into the lung and the 5-HT concentration in the effluent times the flow rate and (2) extrapolation of the rate of appearance of radioactivity in the effluent to zero time. With these methods, we have confirmed the 5-HT is removed by the lung by a carrier-mediated Na+-dependent transport system. Studies of transport systems in perfused organs required an adequate supply of the chemical to the lung. Supply rates less than removal rate will result in erroneous measurements of the constant removal rate. The relationships between the rate of removal, perfusate concentration and perfusion rate were analyzed.

Animals↗