Editing Lysosome (section)

===Lysosomotropism===

Lysosomotropism refers to the tendency of lipophilic weak bases to accumulate in acidic organelles like lysosomes. While neutral forms of these compounds cross membranes easily, their protonated (charged) forms become trapped inside lysosomes, leading to concentrations up to 1000 times higher than outside the cell.<ref>{{cite journal |last1=de Duve |first1=Christian |last2=de Barsy |first2=Thierry |last3=Poole |first3=Brian |last4=Trouet |first4=André |last5=Tulkens |first5=Paul |last6=van Hoof |first6=François |title=Lysosomotropic agents |journal=Biochemical Pharmacology |date=September 1974 |volume=23 |issue=18 |pages=2495–2531 |doi=10.1016/0006-2952(74)90174-9 |pmid=4606365 }}</ref><ref>{{cite book |doi=10.1016/s0091-679x(08)61717-3 |chapter=Chapter 12 Lysosomal Proton Pump Activity: Supravital Cell Staining with Acridine Orange Differentiates Leukocyte Subpopulations |title=Flow Cytometry Second Edition, Part A |series=Methods in Cell Biology |date=1994 |last1=Traganos |first1=Frank |last2=Darzynkiewicz |first2=Zbigniew |volume=41 |pages=185–194 |pmid=7532261 |isbn=978-0-12-564142-5 }}</ref> This “acid trapping” or “proton pump” effect can be predicted using mathematical models.<ref>{{cite journal |last1=Trapp |first1=Stefan |last2=Rosania |first2=Gus R. |last3=Horobin |first3=Richard W. |last4=Kornhuber |first4=Johannes |title=Quantitative modeling of selective lysosomal targeting for drug design |journal=European Biophysics Journal |date=October 2008 |volume=37 |issue=8 |pages=1317–1328 |doi=10.1007/s00249-008-0338-4 |pmc=2711917 |pmid=18504571 }}</ref>

Many approved drugs, including haloperidol,<ref>{{cite journal |last1=Kornhuber |first1=Johannes |last2=Schultz |first2=Andreas |last3=Wiltfang |first3=Jens |last4=Meineke |first4=Ingolf |last5=Gleiter |first5=Christoph H. |last6=Zöchling |first6=Robert |last7=Boissl |first7=Karl-Werner |last8=Leblhuber |first8=Friedrich |last9=Riederer |first9=Peter |title=Persistence of Haloperidol in Human Brain Tissue |journal=American Journal of Psychiatry |date=June 1999 |volume=156 |issue=6 |pages=885–890 |doi=10.1176/ajp.156.6.885 |pmid=10360127 }}</ref> levomepromazine,<ref>{{cite journal |last1=Kornhuber |first1=J. |last2=Weigmann |first2=H. |last3=Röhrich |first3=J. |last4=Wiltfang |first4=J. |last5=Bleich |first5=S. |last6=Meineke |first6=I. |last7=Zöchling |first7=R. |last8=Härtter |first8=S. |last9=Riederer |first9=P. |last10=Hiemke |first10=C. |title=Region specific distribution of levomepromazine in the human brain |journal=Journal of Neural Transmission |date=March 2006 |volume=113 |issue=3 |pages=387–397 |doi=10.1007/s00702-005-0331-3 |pmid=15997416 }}</ref> and amantadine,<ref>{{cite journal |last1=Kornhuber |first1=J. |last2=Quack |first2=G. |last3=Danysz |first3=W. |last4=Jellinger |first4=K. |last5=Danielczyk |first5=W. |last6=Gsell |first6=W. |last7=Riederer |first7=P. |title=Therapeutic brain concentration of the NMDA receptor antagonist amantadine |journal=Neuropharmacology |date=July 1995 |volume=34 |issue=7 |pages=713–721 |doi=10.1016/0028-3908(95)00056-C |pmid=8532138 }}</ref> exhibit lysosomotropic behavior. This helps explain their high tissue-to-blood concentration ratios and prolonged tissue retention, though fat solubility also contributes.

Some lysosomotropic drugs can interfere with lysosomal enzymes like acid sphingomyelinase.<ref>{{cite journal |last1=Kornhuber |first1=Johannes |last2=Tripal |first2=Philipp |last3=Reichel |first3=Martin |last4=Terfloth |first4=Lothar |last5=Bleich |first5=Stefan |last6=Wiltfang |first6=Jens |last7=Gulbins |first7=Erich |title=Identification of New Functional Inhibitors of Acid Sphingomyelinase Using a Structure−Property−Activity Relation Model |journal=Journal of Medicinal Chemistry |date=2008 |volume=51 |issue=2 |pages=219–237 |doi=10.1021/jm070524a |pmid=18027916 }}</ref><ref>{{Cite journal |last1=Kornhuber |first1=Johannes |last2=Muehlbacher |first2=Markus |last3=Trapp |first3=Stefan |last4=Pechmann |first4=Stefanie |last5=Friedl |first5=Astrid |last6=Reichel |first6=Martin |last7=Mühle |first7=Christiane |last8=Terfloth |first8=Lothar |last9=Groemer |first9=Teja W. |last10=Spitzer |first10=Gudrun M. |last11=Liedl |first11=Klaus R. |last12=Gulbins |first12=Erich |last13=Tripal |first13=Philipp |date=2011-08-31 |title=Identification of Novel Functional Inhibitors of Acid Sphingomyelinase |journal=PLOS ONE |volume=6 |issue=8 |pages=e23852 |doi=10.1371/journal.pone.0023852 |doi-access=free |pmc=3166082 |pmid=21909365 |bibcode=2011PLoSO...623852K }}</ref> Ambroxol, a mucolytic, promotes lysosomal exocytosis by neutralizing lysosomal pH and releasing stored calcium.<ref>{{cite journal |last1=Marshall |first1=Kirsty |last2=Easton |first2=Chris |title=The role of asset-based approaches in community nursing |journal=Primary Health Care |date=25 July 2018 |volume=28 |issue=5 |pages=35–38 |doi=10.7748/phc.2018.e1339 }}</ref> This action may underlie its observed benefits in diseases linked to lysosomal dysfunction, including Parkinson's disease and lysosomal storage disorders.<ref>{{cite journal |last1=Albin |first1=Roger L. |last2=Dauer |first2=William T. |title=Magic shotgun for Parkinson's disease? |journal=Brain |date=May 2014 |volume=137 |issue=5 |pages=1274–1275 |doi=10.1093/brain/awu076 |pmid=24771397 }}</ref><ref>{{Cite journal |last1=McNeill |first1=Alisdair |last2=Magalhaes |first2=Joana |last3=Shen |first3=Chengguo |last4=Chau |first4=Kai-Yin |last5=Hughes |first5=Derralyn |last6=Mehta |first6=Atul |last7=Foltynie |first7=Tom |last8=Cooper |first8=J. Mark |last9=Abramov |first9=Andrey Y. |last10=Gegg |first10=Matthew |last11=Schapira |first11=Anthony H. V. |date=May 2014 |title=Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells |journal=Brain: A Journal of Neurology |volume=137 |issue=Pt 5 |pages=1481–1495 |doi=10.1093/brain/awu020 |pmc=3999713 |pmid=24574503 }}</ref>