Glutathione reductase-deficient erythrocytes as host cells of malarial parasites.
BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea] and its less toxic derivative HeCNU [1-(2-chloroethyl)-3-(2-hydroxyethyl)-1-nitrosourea] are clinically-used antitumour drugs. In erythrocytes BCNU is a highly specific inhibitor of the enzyme glutathione reductase [H. Frischer and T. Ahmad, J. Lab. clin. Med. 89, 1080 (1977)]. When treating erythrocytes in vitro, 50% enzyme inhibition was obtained with 1 microM BCNU or 3 microM HeCNU within 2 hr. The two drugs were used for preparing red cell populations with various levels of glutathione reductase activity; complete inhibition (greater than or equal to 98%) was only achieved when the medium contained glucose as a source of reducing equivalents. The erythrocytes were then tested in drug-free media as host cells for the malaria parasite Plasmodium falciparum. In the range of 0-300 mU/ml cells, there was a correlation between glutathione reductase activity and parasite growth; erythrocytes with an activity of less than 20 mU/ml did not serve as host cells for P. falciparum at all although these erythrocytes were viable. When the culture medium was supplemented with 20 mM glutathione (GSH), parasite growth was normal irrespective of the glutathione reductase level in the erythrocytes. This is consistent with the finding that poisoning glutathione reductase led to a 10-fold decrease of the cytosolic GSH level. Our results corroborate the concept that intraerythrocytic inhibition of glutathione reductase mimicks the biochemistry of drug-sensitive glucose-6-phosphate dehydrogenase deficiency (favism), an inherited condition which confers protection from malaria.
Zhang
Y
Y
Institut für Biochemie II, Universität Heidelberg, Federal Republic of Germany.
König
I
I
Schirmer
R H
RH
D000818:Animals; D002330:Carmustine / Q000494:pharmacology; D003470:Culture Media; D004912:Erythrocytes / Q000201:enzymology / Q000469:parasitology*; D005947:Glucose / Q000494:pharmacology; D005980:Glutathione Reductase / Q000097:blood / Q000172:deficiency*; D008288:Malaria / Q000097:blood / Q000201:enzymology*; D009607:Nitrosourea Compounds / Q000494:pharmacology; D010963:Plasmodium falciparum
D003470:Culture Media; D009607:Nitrosourea Compounds; D005980:Glutathione Reductase; D005947:Glucose; C013876:elmustine; D002330:Carmustine