Published permeability coefficient (Kp) data for the transport of a large group of compounds through mammalian epidermis were analyzed by a simple model based upon permeant size [molecular volume (MV) or molecular weight (MW)] and octanol/water partition coefficient (Koct). The analysis presented is a facile means to predict the percutaneous flux of pharmacological and toxic compounds solely on the basis of their physicochemical properties. Furthermore, the derived parameters of the model have assignable biophysical significance, and they provide insight into the mechanism of molecular transport through the stratum corneum (SC). For the very diverse group of chemicals considered, the results demonstrate that SC intercellular lipid properties alone are sufficient to account for the dependence of Kp upon MV (or MW) and Koct. It is found that the existence of an “aqueous-polar (pore) pathway” across the SC is not necessary to explain the Kp values of small, polar nonelectrolytes. Rather, their small size, and consequently high diffusivity, accounts for their apparently larger-than-expected Kp. Finally, despite the size and breadth of the data set (more than 90 compounds with MW ranging from 18 to >750, and log Koct ranging from −3 to + 6), the postulated upper limiting value of Kp for permeants of very high lipophilicity cannot be determined. However, the analysis is able to define the physicochemical characteristics of molecules which should exhibit these maximal Kp values. Overall, then, we present a facile interpretation of a considerable body of skin permeability measurements that (a) very adequately describes the dependence of Kp upon permeant size and lipophilicity, (b) generates parameters of considerable physicochemical and mechanistic relevance, and (c) implies that the SC lipids alone can fully characterize the barrier properties of mammalian skin.

Predicting skin permeability.

A ROLE for abnormal lipid metabolism in the pathogenesis of atherosclerosis was suggested over a century ago, when Virchow proposed that transport of plasma lipids into the walls of blood vessels contributed to the development of atheromatous lesions. Lipid abnormalities are now firmly established as one factor leading to ischemic heart disease, although the mechanism by which they lead to coronary artery occlusion remains incompletely understood. More recently, abnormalities of lipid metabolism have been implicated in another quite different aspect of the pathogenesis of ischemic heart disease. A large body of evidence now indicates that altered lipid metabolism can alter cardiac function by changing the properties of cardiac cell membranes, and that these functional changes may contribute to the decline in myocardial contractility, the arrhythmias, and the eventual cell death that follow coronary artery occlusion. This article will review some of these disorders in lipid metabolism and possible mechanisms by which they might modify membrane function in the ischemic heart. Disorders of Lipid Metabolism in the Ischemic Heart There are now at least three well-defined mechanisms by which lipid metabolism may be altered in the heart after coronary artery occlusion (Table 1). Each of these mechanisms has been implicated in the pathogenesis of the cardiac abnormalities seen in patients who sustain an acute myocardial infarction.

BRIEF REVIEWS Lipid-Membrane Interactions and the Pathogenesis of Ischemic Damage in the Myocardium

Lipid-membrane interactions and the pathogenesis of ischemic damage in the myocardium.

Important constraints on possible molecular mechanisms of general anaesthesia are derived from a quantitative reappraisal of data on the potency of general anaesthetics on whole animals. Despite their popularity, theories that invoke lipids as the prime target do not look at all promising, and available data point much more plausibly to a direct effect on particularly sensitive proteins. Structural changes of proteins on binding general anaesthetics are probably small but may be sufficient to perturb normal function; alternatively, anaesthetics may compete with an endogenous ligand. The phenomenon of pressure reversal of anaesthesia may simply be due to anaesthetics being squeezed away from their target sites.

Molecular mechanisms of general anaesthesia

The well-known correlation between the hydrophobicity of narcotic chemicals and the exposure concentration needed to produce an effect indicates that a lipid phase in the aquatic organism is the most likely target. The molar concentration in aquatic organisms at death is found to be approximately constant for different narcotic chemicals, varying from 2 to 8 mmol/kg organism. Because the proportion of lipid is known, the lethalin vivo membrane burden can be calculated to be 40 to 160 mmol/kg lipid.The exact mechanism underlying narcosis is still unknown. However, disturbance by narcotic chemicals in model membrane systems has been investigated, attention having been paid to disturbance of phospholipids and proteins, and of the interaction between the two groups. Model membrane burdens of different chemicals have been shown to be approximately constant for a particular effect. Different effects are found at different membrane concentrations.In the present review, the toxicity of narcotic chemicals ...

Narcosis due to environmental pollutants in aquatic organisms: residue-based toxicity, mechanisms, and membrane burdens.

IT is generally accepted that neutral anaesthetics, such as the n-alkanols and n-alkanes, act from a hydrophobic site1. Discussion has tended to focus on the nature of this site and, particularly, whether it is located in a membrane protein or in the interior of a bilayer2,3. If the site is in a bilayer then the question arises as to how the proteins involved in nervous impulse propagation are affected. We present here new evidence concerning the anaesthetic properties of the n-alkanes which points to the bilayer as the site of action and also suggests a mechanism for the inhibition of impulse propagation. Briefly, the cut-off in anaesthetic potency on ascending the homologous series is found to be closely related to the decrease in adsorption of the alkane into a cholesterol-containing bilayer. In addition, the anaesthetic hydrocarbons produce a concentration-dependent increase in bilayer thickness. On the basis of these two observations, and from our knowledge of the properties of the ion channel-forming polypeptide gramicidin A (ref. 4) we propose that a thickening of the bilayer regions of the nerve membrane by the alkanes destabilises the open ionic channels formed during electrical excitation.

S R Levinson

Papers

The molecular mechanisms of anaesthesia

Anaesthesia by the n-alkanes. A comparative study of nerve impulse blockage and the properties of black lipid bilayer membranes.

The molecular mechanisms of anesthesia