Passive diffusion of non-electrolytes across the lysosome membrane

Abstract

An osmotic-protection method has been used to study the permeability of rat liver lysosomes to 43 organic non-electrolytes of formula weights ranging from 62 to 1000. A lysosome-rich centrifugal fraction of rat liver homogenate was resuspended in an unbuffered 0.25 M solution of test solute, pH 7.0, and incubated at 25 degrees C for 60 min. The free and total activities of 4-methylumbelliferyl N-acetyl-beta-D-glucosaminidase were measured after incubation for 0, 30 and 60 min. Three patterns of results were seen. In pattern A the percentage free activity remained low throughout the 60 min incubation, indicating little or no solute entry into the lysosomes. In pattern B, the percentage free activity was initially low, but rose substantially during the incubation, indicating solute entry. In pattern C there was not even initial osmotic protection, indicating very rapid solute entry. The rapidity of solute entry into the lysosomes showed no correlation with the formula weight, but a perfect inverse correlation with the hydrogen-bonding capacity of the solutes. The results, which can be used to predict the ability of further compounds to cross the lysosome membrane by unassisted diffusion, are discussed in the context of metabolite and drug release from lysosomes in vivo.

Intestinal permeability to polyethyleneglycol and sugars: a re-evaluation

“…A study of the permeation of non-electrolytes across the rat liver lysosome membrane [6] yielded results that echo those of Maxton et al [1]. Within homologous series of either the sugars, the sugar alcohols or PEG, a good correlation with molecular mass was found.…”

“…The latter is not an experimentally derived value, but one calculated by inspection of a molecule's structural formula and summing the individual (theory-derived) hydrogen-bonding capacities of its functional groups [7]. A near-perfect inverse correlation was observed for all the 43 compounds studied [6]. In light of this outcome and its explanatory potential, the data reported by Maxton et al [1] on intestinal permeability are now reconsidered.…”

“…The degree of polymerization of PEG molecules is shown in parentheses. Hydrogen-bonding capacity is calculated by allocating 2.0 for each alcohol (C-O-H) group and 0.8 for each ether or hemiacetal (C-O-C) group, as previously assigned [6]. Permeability values are in arbitrary units and taken from Figure 2 of [2].…”

Hepatic disposal of advanced glycation end products during maturation and aging

“…It is unknown how AGE-DPs leave the scavenger cells after uptake. Theoretically, free-AGEs and AGE-peptides of various sizes may find their way out of the lysosomes and cells by means of i) membrane transporters (present in both lysosomal end plasma membranes) (Forster and Lloyd, 1988); ii) free diffusion (Forster and Lloyd, 1988; Iveson et al, 1989), iii) retrograde transport along the endocytic pathway (Aniento et al, 1993; Jahraus et al, 1994), or iv) lysosomal exocytosis (Tam et al, 2010). When discussing the mechanism of how AGE-DPs are discharged from the liver scavenger cells, one should bear in mind that most – if not all - such studies have been carried out as short term (minutes – hours) experiments with cells or organelles in vitro, whereas in the present study the time scale is much greater (days-weeks), and takes place in the intact animal.…”

Soluble Polymers as Targetable Drug Carriers

“…However, small non-electrolytes have been found to diffuse across the lysosomal membrance. IVESON et al (1989) have used an osmotic protection method to study the permeability of rat liver lysosomes; 43 organic uncharged molecules were studied (MW 62-1000). From these, three patterns were observed: little or no solute entry into the lysosome, solute entry, and very rapid solute entry.…”