Abstract
Mice infected with Plasmodium berghei served as donors of erythrocytes with a high level of parasitemia for the study of ferriprotoporphyrin IX (FP) polymerization. Six hours after treatment of these mice with 3 micromol of chloroquine per 25 g of body weight, there were significant losses of heme polymerase I (HPA I). For chloroquine-susceptible (CS) P. berghei, the rate of FP polymerization decreased from 541 +/- 42 (mean +/- standard deviation; n = 12) to 51 +/- 19 (n = 8) nmol of FP polymerized per h per ml of packed erythrocytes (normalized to represent 1,000 parasites per 1,000 erythrocytes). For chloroquine-resistant (CR) P. berghei, the rate decreased from 284 +/- 19 (n = 16) to 124 +/- 11 (n = 6) nmol per h per ml. The chloroquine-induced loss of HPA I was accompanied by the accumulation of unpolymerized FP in CS P. berghei but not in CR P. berghei, which is consistent with the hypothesis that FP mediates the antimalarial action of chloroquine. Quinine treatment partially reversed the effects of chloroquine in CS P. berghei but not in CR P. berghei. Cycloheximide treatment antagonized the effects of chloroquine in both lines of parasites. To explain these findings, we propose that chloroquine, quinine, and cycloheximide perturb a regulatory process for HPA I. Furthermore, we propose that when chloroquine engages its target in the regulatory process, it initiates a chain of events which culminates in increased production, accessibility, or reactivity of a regulator (inactivator) of HPA I.
Full Text
The Full Text of this article is available as a PDF (187.0 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Bendrat K., Berger B. J., Cerami A. Haem polymerization in malaria. Nature. 1995 Nov 9;378(6553):138–139. doi: 10.1038/378138a0. [DOI] [PubMed] [Google Scholar]
- Bohle D. S., Dinnebier R. E., Madsen S. K., Stephens P. W. Characterization of the products of the heme detoxification pathway in malarial late trophozoites by X-ray diffraction. J Biol Chem. 1997 Jan 10;272(2):713–716. doi: 10.1074/jbc.272.2.713. [DOI] [PubMed] [Google Scholar]
- Chou A. C., Chevli R., Fitch C. D. Ferriprotoporphyrin IX fulfills the criteria for identification as the chloroquine receptor of malaria parasites. Biochemistry. 1980 Apr 15;19(8):1543–1549. doi: 10.1021/bi00549a600. [DOI] [PubMed] [Google Scholar]
- Chou A. C., Fitch C. D. Control of heme polymerase by chloroquine and other quinoline derivatives. Biochem Biophys Res Commun. 1993 Aug 31;195(1):422–427. doi: 10.1006/bbrc.1993.2060. [DOI] [PubMed] [Google Scholar]
- Chou A. C., Fitch C. D. Heme polymerase: modulation by chloroquine treatment of a rodent malaria. Life Sci. 1992;51(26):2073–2078. doi: 10.1016/0024-3205(92)90158-l. [DOI] [PubMed] [Google Scholar]
- Chou A. C., Fitch C. D. Mechanism of hemolysis induced by ferriprotoporphyrin IX. J Clin Invest. 1981 Sep;68(3):672–677. doi: 10.1172/JCI110302. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dorn A., Stoffel R., Matile H., Bubendorf A., Ridley R. G. Malarial haemozoin/beta-haematin supports haem polymerization in the absence of protein. Nature. 1995 Mar 16;374(6519):269–271. doi: 10.1038/374269a0. [DOI] [PubMed] [Google Scholar]
- Fitch C. D., Chevli R., Banyal H. S., Phillips G., Pfaller M. A., Krogstad D. J. Lysis of Plasmodium falciparum by ferriprotoporphyrin IX and a chloroquine-ferriprotoporphyrin IX complex. Antimicrob Agents Chemother. 1982 May;21(5):819–822. doi: 10.1128/aac.21.5.819. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fitch C. D., Chevli R., Kanjananggulpan P., Dutta P., Chevli K., Chou A. C. Intracellular ferriprotoporphyrin IX is a lytic agent. Blood. 1983 Dec;62(6):1165–1168. [PubMed] [Google Scholar]
- Fitch C. D. Chloroquine resistance in malaria: a deficiency of chloroquine binding. Proc Natl Acad Sci U S A. 1969 Dec;64(4):1181–1187. doi: 10.1073/pnas.64.4.1181. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fitch C. D., Chou A. C. Heat-labile and heat-stimulable heme polymerase activities in Plasmodium berghei. Mol Biochem Parasitol. 1996 Nov 25;82(2):261–264. doi: 10.1016/0166-6851(96)02744-2. [DOI] [PubMed] [Google Scholar]
- Fitch C. D., Kanjananggulpan P. The state of ferriprotoporphyrin IX in malaria pigment. J Biol Chem. 1987 Nov 15;262(32):15552–15555. [PubMed] [Google Scholar]
- Fitch C. D. Mode of action of antimalarial drugs. Ciba Found Symp. 1983;94:222–232. [PubMed] [Google Scholar]
- Fitch C. D., Yunis N. G., Chevli R., Gonzalez Y. High-affinity accumulation of chloroquine by mouse erythrocytes infected with Plasmodium berghei. J Clin Invest. 1974 Jul;54(1):24–33. doi: 10.1172/JCI107747. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Macomber P. B., O'Brien R. L., Hahn F. E. Chloroquine: physiological basis of drug resistance in Plasmodium berghei. Science. 1966 Jun 3;152(3727):1374–1375. doi: 10.1126/science.152.3727.1374. [DOI] [PubMed] [Google Scholar]
- Orjih A. U., Banyal H. S., Chevli R., Fitch C. D. Hemin lyses malaria parasites. Science. 1981 Nov 6;214(4521):667–669. doi: 10.1126/science.7027441. [DOI] [PubMed] [Google Scholar]
- Slater A. F., Cerami A. Inhibition by chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites. Nature. 1992 Jan 9;355(6356):167–169. doi: 10.1038/355167a0. [DOI] [PubMed] [Google Scholar]
- Slater A. F., Swiggard W. J., Orton B. R., Flitter W. D., Goldberg D. E., Cerami A., Henderson G. B. An iron-carboxylate bond links the heme units of malaria pigment. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):325–329. doi: 10.1073/pnas.88.2.325. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Warhurst D. C., Robinson B. L., Howells R. E., Peters W. The effect of cytotoxic agents on autophagic vacuole formation in chloroquine-treated malaria parasites (Plasmodium berghei). Life Sci II. 1971 Jul 8;10(13):761–771. doi: 10.1016/0024-3205(71)90208-6. [DOI] [PubMed] [Google Scholar]