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D Mackay

Publications and source records attributed to D Mackay.

At least 19 recordsLinked to original sources
PubMed1991

Analysis of the binding of fluorescent ligands to soluble proteins. Use of simultaneous non-linear least squares regression to obtain estimates of binding parameters.

The binding of three fluorescent ligands (warfarin, dansylsarcosine and 1-anilino-8-naphthalene sulphonate) to human albumin was analysed using simultaneous non-linear least squares regression analysis. Both mock and actual fluorescence data were examined and the results indicated that reliable estimates of the binding parameters as well as the molar fluorescence of bound ligand could be obtained. The advantage of this method of analysis is that it makes full use of all the experimental data and it eliminates the need for the graphical procedures usually employed to estimate the molar fluorescence of bound ligand and its binding constants. This type of analysis can be extended to other systems where some physical property of the bound ligand varies with increasing protein concentration.

Albumins↗
PubMed1991

The membrane spanning domain of beta-1,4-galactosyltransferase specifies trans Golgi localization.

Chimeric cDNAs were constructed so as to generate hybrid proteins in which different parts of the N-terminal domain of the human invariant chain were replaced by equivalent sequences from the trans Golgi resident enzyme, beta-1,4-galactosyltransferase. The cytoplasmic and membrane spanning domains of galactosyltransferase were found to be sufficient to retain all of the hybrid invariant chain in trans Golgi cisternae as judged by indirect immunofluorescence, treatment with brefeldin A and immuno-electron microscopy. As few as ten amino acids corresponding to the lumenal half of the membrane spanning domain of the Golgi enzyme sufficed to localize most of the hybrid invariant chain to the trans cisternae. A cytoplasmic domain was necessary for complete retention as assessed by flow cytofluorometry but could be provided either by galactosyltransferase or by invariant chain. This suggests that the cytoplasmic domain plays a role accessory to the membrane spanning domain, the latter mediating compartmental specificity.

Amino Acid Sequence↗
PubMed1991

Interpreting aquatic toxicity QSARs: the significance of toxicant body residues at the pharmacologic endpoint.

Aquatic QSAR investigations employ bioassay data where a biological response is associated with a toxicant concentration in the exposure water. Although convenient this ignores the fundamental principle that the response is more closely related to an amount present in the organism. This problem has been examined using acute toxicity and bioconcentration QSARs employing log Kow as the molecular descriptor. Combining these QSAR relationships enables estimates of the amount of toxicant in organisms to be made. For acute narcosis (50% mortality) the toxicant level in the hydrophobic (lipid) phase of an exposed organism is, as a first approximation, constant at approximately 50 mmol l-1 of lipid. For the acute toxicity of a variety of hydrophobic narcotic organics examined by US EPA-Duluth in tests with fathead minnows, this corresponds to a whole-body residue of about 4 mmol kg-1. Although the level in the hydrophobic phase remains constant, for hydrophilic chemicals (log Kow less than 1.5) the contribution of the hydrophilic (water) phase of the organism dominates and total body residues should be similar to the respective threshold LC50s. This has important implications in simple pharmacokinetic modelling and in interpreting residue levels in organisms collected in environmental monitoring studies.

Animals↗
PubMed1990

Interpretation of relative potencies, relative efficacies and apparent affinity constants of agonist drugs estimated from concentration-response curves.

Differences in the relative potencies of agonists have been used successfully in the past to classify receptors. Such use of agonists can be justified on the basis of ideas and equations developed using the occupancy model of drug action. However the occupancy model makes no allowance for possible complications which may arise when the drug-receptor complex interacts with a transducer-effector system. For some receptor-effector systems use of an equilibrium ternary complex model may be better than use of the occupancy model but the former still does not take into account the possible effect of guanosine-5'-triphosphate on the system. A steady-state version of the ternary complex model has therefore been analysed to explore possible interpretations of relative potencies, relative efficacies and apparent affinity constants estimated from concentration-response curves. It is concluded that for agonists which act on receptors which function through G-proteins these pharmacological parameters may depend on the concentration of the relevant G-protein in the cell membranes and on the intracellular concentrations of guanosine-5'-triphosphate and guanosine-5'-diphosphate. If these concentrations vary appreciably between tissues then the parameters are also likely to vary, even for a single receptor-transducer system. It follows that the use of such agonist parameters to classify receptors or receptor-transducer systems is not likely to be totally dependable. It is also possible that agonists which interact with only one receptor-transducer system may show selectivity between tissues with different concentrations of G-proteins and of guanine nucleotides.

Animals↗
PubMed1990

Solubilities of pesticide chemicals in water. Part I: Environmental physical chemistry.

It is hoped that this review of the equilibrium aqueous solution thermodynamics and environmental partitioning tendencies of chemicals will be valuable in elucidating the behavior of pesticide chemicals in the environment and in promoting the development of more reliable correlations between physical chemical measurements and environmental partitioning coefficients. Ultimately the success of both the thermodynamic and environmental interpretations depend on having reliable, critically reviewed data from both laboratory and the "field."

Chemical Phenomena↗
PubMed1990

Agonist potency and apparent affinity: interpretation using classical and steady-state ternary-complex models.

The relative potencies of agonists have been used in the past to classify receptors. This could be justified on the basis of ideas and equations developed using the occupancy model of drug action. Although attempts have been made recently to develop methods of analysis based on other models, these have not been entirely satisfactory. In this article Dennis Mackay explores possible interpretations of relative potency, apparent affinity and efficacy on the basis of a steady-state ternary-complex model. He concludes that use of these quantities to classify receptor-transducer systems may not be entirely dependable. However the steady-state model can explain why use of agonists to classify receptors has been successful in the past and why properties of agonists deduced from ligand binding studies may differ from their properties deduced from experiments on intact tissues.

Animals↗
PubMed1989

Correlation of tissue, blood, and air partition coefficients of volatile organic chemicals.

The physical chemical factors controlling partition coefficients between air, water, blood, and various tissues are discussed. It is suggested that improved insights into the relations between partition coefficients, which are frequently expressed as correlations, may be obtained by viewing the partition coefficients as ratios of solubilities or pseudosolubilities. A simple, novel correlation approach is developed and applied to 24 volatile organic chemicals, which enables tissue/blood, tissue/air, and blood/air partition coefficients to be estimated from water solubility and vapour pressure. An illustration is presented in which these solubilities are used to calculate the equilibrium distribution of dichloromethane between air, blood, and various tissues.

Air↗
PubMed1988

A novel method for measuring membrane-water partition coefficients of hydrophobic organic chemicals: comparison with 1-octanol-water partitioning.

A novel method of measuring membrane-water partitioning characteristics of very hydrophobic organic chemicals is described. Partition coefficients are reported for a series of halogenated aromatic hydrocarbons of varying molar volume between water and L-a-phosphatidylcholine dimyristoyl (DMPC) membrane vesicles and two solvents, n-hexane and 1-octanol. The results indicate that n-hexane and 1-octanol are satisfactory surrogates for DMPC membranes for chemicals with 1-octanol-water partition coefficients (log KOW) less than 5.5 or molar volumes less than 230 cm3/mol. Chemicals with higher log KOW or molar volume values display marked differences in membrane-water, 1-octanol-water, and n-hexane-water partitioning. Implications for lipid- and organism-water partitioning of hydrophobic chemicals are discussed.

1-Octanol↗
PubMed1988

Application of a mathematical model for two component receptor binding to two high affinity oestrogen binding sites in nuclei from DMBA rat mammary tumours.

Saturation binding of [3H]oestradiol has been determined using exchange conditions, on nuclei from DMBA tumours from rats treated prior to sacrifice with oestradiol and tamoxifen alone or in combination. Application of a model to the binding data enabled the amounts (C2) and apparent dissociation constants (Kdapp) of a second lower affinity binding component to be determined as well as the amount of a higher affinity site (C1) and its dissociation constant (Kd1). Kdapp did not change significantly with any pretreatment but 2 h after oestradiol (5 micrograms) and after tamoxifen alone there was a significant decrease in Kd compared with control. It is suggested that the difference in Kd of the higher affinity binding sites in control and 2 h oestradiol treated animals may be due to the loss of an essential co-factor, possibly cytosolic, when nuclei are isolated in the absence of ligand.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1988

The prevalence of thyroid autoantibodies in dermatitis herpetiformis.

The prevalence of IgG class thyroglobulin and microsomal antibodies, estimated using a sensitive ELISA, was 48% in 115 patients with dermatitis herpetiformis, which was significantly greater than the prevalence of 16% in 107 unselected controls without dermatitis herpetiformis. IgA class thyroid antibodies were found in 29% of dermatitis herpetiformis patients. Overt thyroid disease had been diagnosed in six (5%) of the dermatitis herpetiformis group and a further six patients had elevated TSH levels. The presence of thyroid antibodies was not associated with particular HLA-DR antigens. These results demonstrate the frequent occurrence of thyroid antibodies in dermatitis herpetiformis, although thyroid failure is less commonly associated with this condition. Immune response genes outside the HLA-DR region may be involved in the immune hyper-responsiveness seen in dermatitis herpetiformis which is reflected in the high prevalence of thyroid autoimmunity.

Adolescent↗