Inhibition by chloroquine

Slater, A. F., and Cerami, A. (1992). Inhibition by chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites. Nature 355,167-169. 

Donatelli, P. Marchi, G. Giuliani, L. Gustafsson, L.L. Pacifici, G.M. Stereoselective inhibition by chloroquine of histamine N-methyltrans-ferase in the human liver and brain. Eur. J. Qrn. Pharmacol. 1994, 47, 345-349. 

The binding of 8-amlnoquinollne antlmalarials to DNA conqparable to that with chloroquine has been reported.7° effect on DNA fxmction may be involved with antimalarlal activity. Co-en nne Q which is associated with the mitochondrial oxidation of DPNH and succinate and is present in the metabolism of the parasite has been shown to be inhibited by chloroquine, primaquine, quinacrine and menoctone (IV), thus suggesting diversity of action for antimalarial drags.77... 

The anatomic sites (subcellularly) and the details of the enzymatic processes involved in the hydrolysis of chylomicron cholesteryl esters newly taken up by the liver have not been fully defined. It is clear that one of the major processes consists of receptor-mediated endocytosis of chylomicron remnants, followed by hydrolysis of cholesteryl esters and other remnant components within lysosomes. In rare genetic diseases characterized by lysosomal acid lipase deficiency (Wol-man s disease and cholesteryl ester storage disease), cholesteryl esters accumulate in liver cells and in other tissues as well [see Assmann and Frederickson (1983) for review and references]. An acid cholesteryl ester hydrolase from rat liver lysosomes has been partially purified and characterized (Brown and Sgoutas, 1980 Van Berkel etal., 1980). Enzymatic activity was found in preparations of both parenchymal and nonparenchymal liver cells (Van Berkel et al., 1980). Hydrolysis of chylomicron cholesteryl esters taken up by isolated rat hepatocytes was inhibited by chloroquine (Florin and Nilsson, 1977), an agent which inhibits the action of acid hydrolases in lysosomes. Finally, there is also evidence that the rate of cholesteryl ester hydrolysis may be limited by the rate at which internalized remnant particles are moved to the presumably lysosomal site of hydrolysis (Nilsson, 1977 Florin and Nilsson, 1977 Cooper and Yu, 1978). 

H. S. Rosenkranz and F. S. Southwick, Preferential inhibition by chloroquine and quinacrine of E. coll deficient in DNA polymerase. Environ. Mutat. Soc. Newslett. 5, 38 (1971). 

Ginsburg, H. Famin, O. Zhang, J. Krugliak, M. Inhibition of glutathione-dependent degradation of heme by chloroquine and amodiaquine as a possible basis for their antimalarial mode of action. Biochem. Pharmacol, 1998, 56(10) 1305-1313. 

Reuner KH, Schlegel K, Just I, et al. (1991) Autoregulatory control of actin synthesis in cultured rat hepatocytes. In FEBS Letters. 286 100-4 Schmid A, Benz R, Just I, et al. (1994) Interaction of Olostridium botulinum 02 toxin with lipid bilayer membranes. Formation of cation-selective channels and inhibition of channel function by chloroquine. In J Biol Chem. 269 16706-11 Simpson LL (1982) A comparison of the pharmacological properties of Clostridium botulinum type 01 and 02 toxins. In J Pharmacol Exp Then 223 695-701 Simpson LL (1989a) Botulinum Neurotoxin andTetanus Toxin, pp 1 -422, San Diego Academic Press... 

The most specific metabolizing enzyme is imidazole N-methyl-transferase ( histamine acetylase ), which can be inhibited in vivo by amodiaquine, chloroquine and metoprine. Histamine is also metabolized by hlstaminase , and this enzyme can be inhibited by aminoguanidine, metronidazole and pentamidine (see diamine oxidase inhibitors). Metabolites in the urine can be measured to give some index of histamine turnover. 

Emetine (Fig. 7-9) in the form of the crude drug obtained from the roots and rhizomes of Ipecac (Cephaelis ipecacuanha) has been in use since the seventeenth century. The alkaloid, as the hydrochloride, has been used parenterally to treat amebic dysentery. It is also effective in hepatic infestation, but not against amebic cysts. Because of its cardiac toxicity and emetogenic properties, it has been superseded by metronidazole and chloroquine, but it is still used as an alternative. The amebicidal mechanism of emetine is protein synthesis inhibition by interference of peptidyl-RNA translocation. Since this action is general to eukaryotic cells, its relative selectivity in the presence of mammalian cells is not well understood. Unrelated uses of Ipecac (presumably due to its alkaloid content) are as an expectorant in cough preparations and an emergency emetic (Syrup of Ipecac). 

Lack and Ali have reported that the tissue activator of plasminogen resides in the lysosomal fraction of cell cytoplasm and is inhibited by amino-caproic acid. This is noteworthy, since other workers " have postulated that the anti-inflammatory activity of cortisone may be attributable to its ability to prevent the release of lysosomal proteases by stabilizing the lysosomal membrane. Chloroquine may act similarly . 

Whitehouse , and Whitehouse and Bostrom investigated the incorporation of glucose- G, acetate- G and S04 into mucopolysaccharide sulphates, and the oxidation of glucose- G, acetate-pyruvate- C and octanoate- C in cartilage and cornea. The incorporation of the above substances is inhibited by salicylate, phenylbutazone and cinchophen, all of which have an immediate effect on the reaction, and by hydrocortisone and chloroquine which are effective only after a time lag of 1-2 hours. There seems to be some relationship between the inhibition of uptake by non-steroidal compounds and their anti-inflammatory activities. It is concluded that the drugs diminish anabolic reactions in connective tissue by inhibiting fundamental exergonic reactions. 

Lancaster DL, Adio RA, Tai KK, Simooya 00, Broadhead GD, Tucker GT, Lennard MS. Inhibition of metoprolol metabolism by chloroquine and other antimalarial drugs. JPharm Pharmacol (1990) 42, 267-71. 

It is of interest that in adult rat skeletal muscle whose lysosomal enzyme activities were impaired by chloroquine treatment, AP was accumulated [177, 178]. Our newest studies demonstrated that inhibition of lysosomal activity in cultured human musde fibers induces in them AP oligomerization ([100], and below). 

Chloroquine is the drug of choice for preventing and treating acute forms of malaria caused by P. vivax, P. malariae, P ovale, as well as sensitive forms of P. falciparum. The mechanism of its action is not completely clear, although there are several hypotheses explaining its antimalarial activity. Chloroquine and its analogs inhibit synthesis of nucleic acids of the parasite by affecting the matrix function of DNA. This happens by preliminary... 

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