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Altered Permeability of Cell Membranes

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Abstract

The sections in this article are:

1 Membrane Theory of Toxicity
2 Heavy Metals — Mercury and its Compounds
2.1 Passive Ion and Water Permeability of Cells
2.2 Carrier‐Mediated Ion Transport
2.3 Inhibition of Other Transport Systems
2.4 Environmental Role
3 Organochlorines — DDT and its Metabolites
3.1 Passive Na+ and K+ Permeability of Axolemma
3.2 Active Na+ Transport in Epithelia and Cells
3.3 Inhibition of Other Active Transport Systems
4 Conclusions and Speculations
Figure 1. Figure 1.

Schematic and simplified diagram of generalized cell membrane showing permeability pathways. In mosaic of lipids and proteins composing the membrane, hydrophobic portions of these molecules (stippled) are in the interior; hydrophilic portions (unstippled) constitute the interface between membrane and aqueous media and contain the functional protein groups regulating both passive and carrier‐mediated permeability pathways. Top: ion‐specific aqueous channels, gates, or pores through hydrophilic regions of the membrane used for passive (downhill) movement of electrolytes (and some small water‐soluble nonelectrolytes as well) across the membrane. Associated sulfhydryl (SH) and amino () groups affect the regulation of permeability. Hydrophobic regions of the membrane are used for movement of lipid‐soluble substances. Bottom: representative carrier‐mediated processes. Thick arrows, active transport, i.e., movement against an electrochemical gradient that requires coupling to metabolic energy. This coupling may be either to ATP hydrolysis directly (Na+ pump) or to an ion gradient maintained by a separate pump (Na‐coupled cycloleucine transport). Thin arrows, movement down the electrochemical gradient of the substrate. Black areas at membrane surface, binding sites on carrier for substrate or coupled ion. Sodium pump is shown as electrogenic, yet in many instances active sodium transport is accompanied by simultaneous movement of potassium in the opposite direction. Actual directions of transport into or out of the cell have been ignored.

Adapted from Rothstein et al.
Figure 2. Figure 2.

Inhibition of Na‐dependent (unstippled) cycloleucine accumulation in intestinal tissue of killifish (Fundulus heteroclitus) exposed in vivo to DDT. All fish were adapted to seawater; just prior to removal of tissue for in vitro study, experimental group was exposed for 4 h to 0.075 ppm p,p′‐DDT suspended in seawater by sonication. Continued exposure to this level of DDT for 48 h produced 50% mortality in seawater‐adapted killifish . In study of intestinal transport, cycloleucine is commonly employed to evaluate the neutral amino acid system or systems, since it is nonmetabolized and transported rapidly enough across the brush border into epithelial cells so that these cells can be assumed to be the primary site of tissue uptake during brief incubation in vitro. Present results indicate that, in addition to being DDT‐sensitive, the Na‐dependent component of cycloleucine uptake represents active (uphill) transport against a concentration gradient — i.e., causes the tissue‐to‐medium concentration ratio to exceed unity. Other results (not shown) indicate that this uptake component was fully inhibitable by several naturally occurring neutral amino acids, e.g., leucine, alanine, proline and glycine, and was partially inhibitable by taurine and 3‐amino proprionic acid (β‐alanine). In contrast, the minor Na‐independent component (stippled) was insensitive to neutral amino acids as well as to DDT and probably represents passive diffusion into cells.

Figure 3. Figure 3.

Inhibition of ion‐activated ATPase fractions in duck shell‐gland homogenate by 1,1‐dichloro‐2,2‐bis(p‐chlorophenyl)ethylene (DDE) added in vitro to assay media. Each point represents the mean of 3–10 conventional ATPase assays on tissue from normal, laying domestic ducks (Anas platyrynchos). Mucosal scrapings from freshly killed birds were homogenized, freeze‐dried, and reconstituted in several media, each having the proper ion composition for maximum activation of a particular ATPase. For the anion‐activated enzyme, sulfite was employed, for it yielded more ATPase activity than bicarbonate. DDE concentration was based on quantity added to assay media; 0.5% N,N‐dimethylformamide provided solubilization in the media. Control rates of ATP hydrolysis were measured in the presence of the solvent alone.



Figure 1.

Schematic and simplified diagram of generalized cell membrane showing permeability pathways. In mosaic of lipids and proteins composing the membrane, hydrophobic portions of these molecules (stippled) are in the interior; hydrophilic portions (unstippled) constitute the interface between membrane and aqueous media and contain the functional protein groups regulating both passive and carrier‐mediated permeability pathways. Top: ion‐specific aqueous channels, gates, or pores through hydrophilic regions of the membrane used for passive (downhill) movement of electrolytes (and some small water‐soluble nonelectrolytes as well) across the membrane. Associated sulfhydryl (SH) and amino () groups affect the regulation of permeability. Hydrophobic regions of the membrane are used for movement of lipid‐soluble substances. Bottom: representative carrier‐mediated processes. Thick arrows, active transport, i.e., movement against an electrochemical gradient that requires coupling to metabolic energy. This coupling may be either to ATP hydrolysis directly (Na+ pump) or to an ion gradient maintained by a separate pump (Na‐coupled cycloleucine transport). Thin arrows, movement down the electrochemical gradient of the substrate. Black areas at membrane surface, binding sites on carrier for substrate or coupled ion. Sodium pump is shown as electrogenic, yet in many instances active sodium transport is accompanied by simultaneous movement of potassium in the opposite direction. Actual directions of transport into or out of the cell have been ignored.

Adapted from Rothstein et al.


Figure 2.

Inhibition of Na‐dependent (unstippled) cycloleucine accumulation in intestinal tissue of killifish (Fundulus heteroclitus) exposed in vivo to DDT. All fish were adapted to seawater; just prior to removal of tissue for in vitro study, experimental group was exposed for 4 h to 0.075 ppm p,p′‐DDT suspended in seawater by sonication. Continued exposure to this level of DDT for 48 h produced 50% mortality in seawater‐adapted killifish . In study of intestinal transport, cycloleucine is commonly employed to evaluate the neutral amino acid system or systems, since it is nonmetabolized and transported rapidly enough across the brush border into epithelial cells so that these cells can be assumed to be the primary site of tissue uptake during brief incubation in vitro. Present results indicate that, in addition to being DDT‐sensitive, the Na‐dependent component of cycloleucine uptake represents active (uphill) transport against a concentration gradient — i.e., causes the tissue‐to‐medium concentration ratio to exceed unity. Other results (not shown) indicate that this uptake component was fully inhibitable by several naturally occurring neutral amino acids, e.g., leucine, alanine, proline and glycine, and was partially inhibitable by taurine and 3‐amino proprionic acid (β‐alanine). In contrast, the minor Na‐independent component (stippled) was insensitive to neutral amino acids as well as to DDT and probably represents passive diffusion into cells.



Figure 3.

Inhibition of ion‐activated ATPase fractions in duck shell‐gland homogenate by 1,1‐dichloro‐2,2‐bis(p‐chlorophenyl)ethylene (DDE) added in vitro to assay media. Each point represents the mean of 3–10 conventional ATPase assays on tissue from normal, laying domestic ducks (Anas platyrynchos). Mucosal scrapings from freshly killed birds were homogenized, freeze‐dried, and reconstituted in several media, each having the proper ion composition for maximum activation of a particular ATPase. For the anion‐activated enzyme, sulfite was employed, for it yielded more ATPase activity than bicarbonate. DDE concentration was based on quantity added to assay media; 0.5% N,N‐dimethylformamide provided solubilization in the media. Control rates of ATP hydrolysis were measured in the presence of the solvent alone.

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W. B. Kinter, J. B. Pritchard. Altered Permeability of Cell Membranes. Compr Physiol 2011, Supplement 26: Handbook of Physiology, Reactions to Environmental Agents: 563-576. First published in print 1977. doi: 10.1002/cphy.cp090136