Intracellular distribution and effect of the antimalarial drug mefloquine on lysosomes of rat liver.
Mefloquine was administered in a single dose (1-30 mg/100 g) to rats in order to study its subcellular distribution and effects on rat liver lysosomal structure and function. Subcellular fractionation showed a significant enrichment of mefloquine in lysosomes. Even repeated administration of mefloquine did not affect the levels of cytochrome-P-450 or its reductase, indicating, although not proving, that it is not metabolized by this mono-oxygenase system. Mefloquine caused an expansion of the lysosomal apparatus, earliest seen by 24 h and lasting for some 7 days. Initially, cytoplasmic constituents were seen inside the lysosomes. Later, the lysosomes harboured myelin-like figures (multilamellar bodies) disappearing after 7-10 days. The proteolytic and lipolytic capacity was assessed in isolated lysosomes. Mefloquine caused increased protein degradation but decreased breakdown of lipids. Concomitantly, all five major phospholipids (phosphatidyl-choline, -ethanolamine, -inositol, -serine and sphingomyelin) increased in the lysosomes. It is concluded that: (1) mefloquine is a lysosomotropic drug that accumulates in lysosomes; (2) mefloquine impairs lipid degradation with ensuing accumulation of lipids in lysosomes; and (3) lysosomal trapping explains the high volume distribution of mefloquine.
Glaumann
H
H
Department of Pathology, Huddinge University Hospital, Sweden.
Motakefi
A M
AM
Jansson
H
H
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects* / Q000648:ultrastructure; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D015767:Mefloquine / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008854:Microscopy, Electron; D051381:Rats; D017207:Rats, Sprague-Dawley
D003577:Cytochrome P-450 Enzyme System; D015767:Mefloquine