Genetic toxicology testing of the antimalarial drugs chloroquine and a new analog, AQ‐13
- 1 January 2001
- journal article
- research article
- Published by Wiley in Environmental and Molecular Mutagenesis
- Vol. 38 (1), 69-79
- https://doi.org/10.1002/em.1052
Abstract
AQ‐13 ([N1‐(7‐chloro‐quinolin‐4yl)‐3‐(N3,N3‐diethylamino)propylamine] dihydrochloride trihydrate) is an aminoquinoline antimalarial drug that is effective against chloroquine‐resistant strains of Plasmodium falciparum. It is structurally similar to the widely used chloroquine diphosphate (CQ). We evaluated these drugs in the three assays currently recommended by the International Conference on Harmonization (ICH): bacterial mutagenesis in Salmonella typhimurium and Escherichia coli, mammalian cell mutagenesis in L5178Y mouse lymphoma cells, and micronucleus induction in rat bone marrow. A small but statistically significant increase in revertant colonies was produced by CQ with Salmonella tester strain TA98 without metabolic activation (MA) and by AQ‐13 with strain TA1537 both with and without MA. In L5178Y cells, testing of CQ and AQ‐13 up to cytotoxic concentrations with and without MA produced no increase in mutant colonies and no increase in the numbers of small colonies. Slight decreases in the ratio of polychromatic erythrocytes (PCE) to red blood cells (RBC) were observed in male and female rats treated with CQ and in females only treated with AQ‐13; however, none of these changes was statistically significant. No increases in the frequency of micronucleated PCE were observed at any dose level of CQ or AQ‐13. Although both CQ and AQ‐13 showed weak bacterial mutagenicity, this mutagenic effect was not confirmed in either the mouse lymphoma mutagenesis assay or the micronucleus assay. These results indicate that CQ and AQ‐13 should pose minimal risk of genotoxic damage in human populations being administered these drugs. Environ. Mol. Mutagen. 38:69–79, 2001Keywords
This publication has 20 references indexed in Scilit:
- Comparative mutagenic and genotoxic effects of three antimalarial drugs, chloroquine, primaquine and amodiaquineMutagenesis, 1998
- Aminoquinolines That Circumvent Resistance in Plasmodium falciparum in VitroThe American Journal of Tropical Medicine and Hygiene, 1996
- Uptake and efflux of chloroquine by chloroquine-resistant Plasmodium falciparum clones recently isolated in AfricaActa Tropica, 1994
- Beyond Chloroquine: Implications of Drug Resistance for Evaluating Malaria Therapy Efficacy and Treatment Policy in AfricaThe Journal of Infectious Diseases, 1993
- Mutagenicity of urine from mice exposed orally to nitrite and various aminated antiparasitic drugsEnvironmental and Molecular Mutagenesis, 1989
- Genotoxicity of amebicide and anthelmintic drugs in Escherichia coli pol A+/pol A−Mutation Research/Genetic Toxicology, 1987
- Mutagenicity of antiamebic and anthelmintic drugs in the Salmonella typhimurium microsomal test systemMutation Research/Genetic Toxicology, 1983
- An evaluation of the Escherichia coli WP2 and WP2uvrA reverse mutation assayMutation Research/Reviews in Genetic Toxicology, 1980
- Some Remarks on Exact Confidence Intervals for Positive Linear Combinations of Variance ComponentsJournal of the American Statistical Association, 1980
- Methods for detecting carcinogens and mutagens with the salmonella/mammalian-microsome mutagenicity testMutation Research/Environmental Mutagenesis and Related Subjects, 1975