Morphometric Studies on Terminal Tubule and Acinar Cells in Developing Submandibular Gland of the Rat.

Taga, Rumio; Alvares, Eliana Parisi; Sesso, Antônio

doi:10.1679/aohc.56.517

Cited by 4 publications

(3 citation statements)

References 16 publications

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“…The relevant parameters (voltage, pH, and fractional volume) for estimating the unbound partitioning within muscle (Guderley et al, 2006;Sawant et al, 2011), liver (Peters, 1984;Saito et al, 1992;Plettenberg et al, 2008), and the pancreas (Nishiyama and Petersen, 1974;Morgan et al, 1986;Taga et al, 1993) are provided in Table 1. The key approximation that will be made within this framework is that the transmembrane permeation is similar across various cell and organelle types and that fu is a whole tissue parameter.…”

Section: Methodsmentioning

confidence: 99%

Toward a Unified Model of Passive Drug Permeation II: The Physiochemical Determinants of Unbound Tissue Distribution with Applications to the Design of Hepatoselective Glucokinase Activators

Ghosh

Maurer

Litchfield

et al. 2014

Drug Metabolism and Disposition

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In this work, we leverage a mathematical model of the underlying physiochemical properties of tissues and physicochemical properties of molecules to support the development of hepatoselective glucokinase activators. Passive distribution is modeled via a Fick-Nernst-Planck approach, using in vitro experimental data to estimate the permeability of both ionized and neutral species. The model accounts for pH and electrochemical potential across cellular membranes, ionization according to Henderson-Hasselbalch, passive permeation of the neutral species using Fick's law, and passive permeation of the ionized species using the NernstPlanck equation. The mathematical model of the physiochemical system allows derivation of a single set of parameters governing the distribution of drug molecules across multiple conditions both in vitro and in vivo. A case study using this approach in the development of hepatoselective glucokinase activators via organic anion-transporting polypeptide-mediated hepatic uptake and impaired passive distribution to the pancreas is described. The results for these molecules indicate the permeability penalty of the ionized form is offset by its relative abundance, leading to passive pancreatic exclusion according to the Nernst-Planck extension of Fickian passive permeation. Generally, this model serves as a useful construct for drug discovery scientists to understand subcellular exposure of acids or bases using specific physiochemical properties.

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Section: Methodsmentioning

confidence: 99%

Toward a Unified Model of Passive Drug Permeation II: The Physiochemical Determinants of Unbound Tissue Distribution with Applications to the Design of Hepatoselective Glucokinase Activators

Ghosh

Maurer

Litchfield

et al. 2014

Drug Metabolism and Disposition

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“…We used surface areas, S, and volumes, V, of ER and Golgi as determined from terminal tubule and acinar cells of the rat submandibular gland (32); S and V of MSGs were based on a 200-m diameter sphere (33). Although our H ϩ permeability calculations were determined for AtT-20 (mouse anterior pituitary) cells, we used the S and V values from Taga et al (32) because this was the only published report where S and V for both ER and Golgi membranes were measured in the same cell type.…”

Section: Methodsmentioning

confidence: 99%

“…mM/pH) were determined (as described under "Experimental Procedures") for the cytosol (23 Ϯ 3, n ϭ 38), ER (17 Ϯ 3, n ϭ 21), Golgi (26 Ϯ 6, n ϭ 10), and MSG (20 Ϯ 6, n ϭ 10) compartments. By using these mean buffer capacity values and previously estimated surface areas and volumes (32,33), the data from acid-load recovery experiments (Fig. 4B) were fit (Fig.…”

Section: ϫ4mentioning

confidence: 99%

Mechanisms of pH Regulation in the Regulated Secretory Pathway

Wu¹,

Grabe²,

Adams³

et al. 2001

Journal of Biological Chemistry

240

224

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A precise pH gradient between organelles of the regulated secretory pathway is required for sorting and processing of prohormones. We studied pH regulation in live endocrine cells by targeting biotin-based pH indicators to cellular organelles expressing avidin-chimera proteins. In AtT-20 cells, we found that steady-state pH decreased from the endoplasmic reticulum (ER) (pH ER ‫؍‬ 7.4 ؎ 0.2, mean ؎ S.D.) to Golgi (pH G ‫؍‬ 6.2 ؎ 0.4) to mature secretory granules (MSGs) (pH MSG

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Post‐Natal Maturation of Acinar Cells of the Guinea Pig Pancreas: An Ultrastructural Morphometric Study

Assis

Cestari

Sesso

et al. 2003

Anat Histol Embryol

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The morphological maturation of the acinar cells of the guinea pig pancreas during post-natal development was characterized morphometrically by determining the intracytoplasmic accumulation of rough endoplasmic reticulum (RER) and zymogen granules. The following results were obtained for the period analysed, i.e., from 2 to 70 days of post-natal life: (a) the acinar cell volume increased by 210% (P < 0.01); (b) the mostly cisternal RER occupied more than 30% of the cytoplasm at any age studied and their total volume and surface in the cell were increased by 300 and 534% (P < 0.01), respectively; (c) maturation in the morphological pattern of the RER was observed; (d) the mean number of zymogen granules per cell increased from 261 at 2 days to 422 at 70 days (P < 0.01), while their mean diameter increased from 0.52 to 0.94 micron (P < 0.01) during the same period; (e) these increases in granule number and size were responsible for a 500% (P < 0.01) increase in total volume from 2 to 70 days and for a 304% increase (P < 0.01) in total surface from 2 to 35 days; (f) the RER and the zymogen granules together occupied 44, 54, 55 and 57% of the cytoplasm at 2, 14, 35 and 70 days of age, respectively. We conclude that although the pancreatic acinar cells of the guinea pig are morphologically well differentiated at 2 days of age, with the cytoplasm already showing a large amount of RER and zymogen granules, they are still immature. Morphological maturation of the acinar cell occurs during the first months of post-natal life and is characterized by a substantial gain in cell volume and intracytoplasmic accumulation of RER and zymogen granules, which significantly increase of both their absolute volume and total surface, with a higher growth rate being observed during the period from 2 to 14 days of post-natal life.

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Morphometric Studies on Terminal Tubule and Acinar Cells in Developing Submandibular Gland of the Rat.

Cited by 4 publications

References 16 publications

Toward a Unified Model of Passive Drug Permeation II: The Physiochemical Determinants of Unbound Tissue Distribution with Applications to the Design of Hepatoselective Glucokinase Activators

Toward a Unified Model of Passive Drug Permeation II: The Physiochemical Determinants of Unbound Tissue Distribution with Applications to the Design of Hepatoselective Glucokinase Activators

Mechanisms of pH Regulation in the Regulated Secretory Pathway

Post‐Natal Maturation of Acinar Cells of the Guinea Pig Pancreas: An Ultrastructural Morphometric Study

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