| Mechanism of protection afforded by polyaspartic acid against gentamicin-induced phospholipidosis. II. Comparative in vitro and in vivo studies with poly-L-aspartic, poly-L-glutamic and poly-D-glutamic acids. | |
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MedLine Citation:
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PMID: 1700819 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Poly-L-aspartic acid (poly-L-Asp) protects rats against gentamicin (GM)-induced nephrotoxicity (functional and pathological changes) and early cortical alterations (phospholipidosis and increase in cell turnover) without decreasing, but actually increasing, the renal accumulation of the drug. We suggested that this protection occurs through the complexation of GM by poly-L-Asp, after their pinocytosis and accumulation in the lysosomes of the renal cortex (Kishore et al., J. Pharmacol. Exp. Ther. 867-874, 1990). Here we examine further our proposal by comparatively assessing poly-L-Asp (as provided by the Sigma Chemical Co., St. Louis, MO; MW 9-11,000), with two other polyanionic peptides, viz, poly-L-glutamic (poly-L-Glu; MW 14,300) and poly-D-glutamic (poly-D-Glu; MW 20,000) acids obtained from the same supplier. In vitro, all three polyanions showed a similar capacity to bind GM, to displace it from anionic phospholipids at acid pH and thereby to decrease the inhibitory potency of GM toward lysosomal phospholipase A1. In vivo, however, only poly-L-Asp and poly-D-Glu were able to prevent the development of GM-induced renal lysosomal phospholipidosis as assessed by key biochemical criteria (increase in lipid phosphorus and decrease of acid sphingomyelinase activity) and by examination of the lysosomal content in the electron microscope (accumulation of myeloid bodies). Based on these criteria, poly-L-Glu completely failed to protect. In vitro, poly-L-Glu was 13- to 17-fold more susceptible to hydrolysis by liver lysosomal extracts at pH 5.4 after 48 hr incubation, as compared to poly-L-Asp and poly-D-Glu, respectively. Assuming that all three polyanions tested are transported and accumulated in lysosomes of renal cortex to the same extent and that their respective rates of hydrolysis therein compare to that measured in vitro, these results suggest that stability of polyanions in lysosomes is an essential requisite for protection against GM-induced phospholipidosis and thus strengthens our earlier proposal that the site of action of poly-L-Asp must be in lysosomes. Although protecting from phospholipidosis, poly-D-Glu, however, caused a so far undescribed lysosomal storage disorder consisting of the accumulation of osmiophilic, nonlamellar material. This study, therefore, also demonstrates that not all polyanions resistant to lysosomal enzymes can be used as nephroprotectants, inasmuch as these, as is the case for poly-D-Glu, may cause renal alterations on their own. |
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Authors:
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B K Kishore; P Lambricht; G Laurent; P Maldague; R Wagner; P M Tulkens |
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Publication Detail:
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Type: Comparative Study; In Vitro; Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 255 ISSN: 0022-3565 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 1990 Nov |
Date Detail:
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Created Date: 1990-12-31 Completed Date: 1990-12-31 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 875-85 Citation Subset: IM |
Affiliation:
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Laboratoire de Chimie Physiologique, Université Catholique de Louvain, Bruxelles, Belgium. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Female Gentamicins / metabolism, toxicity* Kidney / drug effects*, metabolism, pathology Liposomes / metabolism Lysosomes / drug effects, metabolism Peptides / metabolism, pharmacology* Phospholipases A / antagonists & inhibitors Phospholipases A1 Phospholipids / metabolism* Polyglutamic Acid / metabolism, pharmacology* Rats Rats, Inbred Strains Stereoisomerism |
| Chemical | |
Reg. No./Substance:
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0/Gentamicins; 0/Liposomes; 0/Peptides; 0/Phospholipids; 25513-46-6/Polyglutamic Acid; 26063-13-8/polyaspartate; EC 3.1.1.-/Phospholipases A; EC 3.1.1.32/Phospholipases A1 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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