Total synthesis of the four stereoisomers of dihexadecanoyl phosphatidylinositol and the substrate stereospecificity of human erythrocyte membrane phosphatidylinositol 4-kinase

A new and convenient method for the preparation of the four stereoisomers of dihexadecanoyl phosphatidylinositol has been developed. An enantiomeric pair of acid-labile, pentaprotected myo-inositol building blocks was synthesized in high yield and coupled with chiral phenyl dihexadecanoylglyceryl phosphates to give the fully protected phosphatidylinositols. These were subsequently deprotected by hydrogenolysis and self-hydrolysis in aqueous ethanol to give the desired pure products. Comparison of these compounds as potential substrates for a partially purified phosphatidylinositol 4-kinase (EC 2.7.1.67) derived from human erythrocyte membranes revealed that the chirality of the inositol ring is crucial for efficient phosphorylation, whereas the chirality of the glycerol moiety is relatively unimportant. Moreover, the similarity in phosphorylation rates of the naturally occurring mammalian phospholipid, I, and its synthetic stereochemical counterpart, compound 10a, suggests that the enzyme is relatively tolerant to changes in fatty acid composition.     

Pulmonary clearance of UICC amosite fibres inhaled by rats during chronic exposure at low concentration.

Clearance of UICC amosite asbestos from the lungs during chronic--that is, repeated--exposure was investigated by using the scanning electron microscope to measure lung burdens from rats which had inhaled amosite asbestos at an approximately constant concentration of 0.1 mg/m3 or, equivalently, 20 fibres/ml for seven hours a day, five days a week for up to 18 months. The lung burdens were compared with previous results for higher exposure concentrations of 1 and 10 mg/m3. Those previous lung burdens had been measured using other analytical methods (infrared spectrophotometry) that were not suitable for the new lower lung burdens. Taken together, these results showed lung burdens rising pro rata with exposure concentration and exposure time. This accumulation of lung burden has been described by a kinetic model that takes account of the sequestration of material at locations in the lung from where it cannot be cleared. Unlike some earlier models in which lung burdens eventually reach a plateau with equilibrium between deposition and clearance during chronic exposure, this sequestration model shows lung burdens continuing to rise with exposure time. The latest results reported here support the application of such a model to lower exposure concentrations closer to those of asbestos in workplaces.     

Relation between toxicity and carcinogenesis in the kidney: an heuristic hypothesis

Cellular toxicity and cellular carcinogenesis are closely linked. In the kidney, this relationship has been emphasized by the recent discovery of a number of putatively non-mutagenic chemicals that result in acute and chronic toxicity and ultimately in carcinogenesis, especially in the male rat. Many, but not all such compounds, result in renal PTE phagolysosomal overload. At the same time, known metabolites of other carcinogens, e.g., HCBD and FBPA, result in acute renal injury and/or necrosis, followed by chronic tubular disease, interstitial nephritis, and ultimately carcinogenesis. A series of cell mechanisms have been suggested that lead from acute cell injury to altered control of cell division. These mechanisms appear to involve ion deregulation, (especially [Ca2+]i) resulting from a variety of continued injuries, (e.g., oxidative stress from inflammatory cells) and ultimately leading to altered gene expression.     

Genetics: Changing Health Care in the 21st Century

Advances in human genetics are rapidly changing the scope of information and care that can be provided to health care consumers. By the year 2005 it is expected that the entire human genome will be mapped and all 70,000–100,000 genes will be identified. Currently, there are more than 5,000 known single-gene disorders. With the movement of specialized health services into the primary care setting, nurses increasingly will need to be knowledgeable about genetic disorders, screening/diagnostic tests, and implications for health care. In addition, the management of genetic information raises issues of informed consent, privacy and confidentiality, truth telling and disclosure, and nondiscrimination.     

The EPC Approach to Estimating Safety from Exposure to Environmental Chemicals

Reference doses (RfDs) and reference concentrations (RfCs) developed by the United States Environmental Protection Agency (USEPA) are typically used in the quantitation of risk of potential adverse human health effects from exposure to environmental chemicals. For a large number of chemicals, however, USEPA RfDs and RfCs have not yet been determined. Thus, for risk assessments that involve a large number of chemicals, there is insufficient toxicity information with which to evaluate potential adverse human health effects for all chemicals present at a particular site. Due to this insufficiency, the risk assessor must either (1) ignore potential exposures on the assumption that omitting these exposures does not significantly alter decisions concerning the remediation of the site or (2) undertake a lengthy and costly analysis to generate the necessary RfDs or RfCs. A potential solution to this problem is to develop estimated permissible concentrations (EPCs), values which represent permissible environmental concentrations or related acceptable daily dosages derived from occupational exposure limits. In the present analysis, acceptable daily dosages determined using the EPC method were compared to USEPA RfDs or RfCs which were converted to dosages based on standard exposure assumptions. Based on a comparative analysis of EPCs and USEPA reference values for 103 chemicals, it was found that EPC daily dosages represent a reasonably conservative surrogate value when USEPA or state reference values are unavailable. Given that there are hundreds of chemicals with occupational exposure limits but no state or USEPA reference values, acceptance of the EPC methodology would provide an interim solution for the problem of insufficient toxicity information for a substantial number of environmental chemical contaminants.