Role of glutathione in the detoxification of ferriprotoporphyrin IX in chloroquine resistant Plasmodium berghei.

Abstract:

:The reduction in hemozoin content is a well known feature of chloroquine-resistant Plasmodium berghei. Using NK65-derived lines displaying increasing resistance levels, we observed an inverse relationship between the hemozoin content, and the glutathione (GSH) and glutathione S-transferase (GST) levels. Treatment of highly chloroquine-resistant-infected mice with buthionine sulfoximine (BSO), which has previously been shown to partially reverse this chloroquine resistance, led to a significant increase in hemozoin production. In vitro studies on the polymerization of ferriprotoporphirin IX (FPIX) at pH 5.0 showed that GSH partially inhibited beta-hematin synthesis, while GST had a trivial and non specific effect. Furthermore, chloroquine-sensitive parasites invading reticulocytes displayed higher GSH level and GST activity, and reduced hemozoin synthesis and susceptibility to chloroquine. We conclude that, in chloroquine resistant P.berghei, GSH can detoxify hemin within the food vacuole, thus precluding its polymerization and preventing the activity of chloroquine and other quinoline-containing drugs. It is proposed that vacuolar GSH could be ascribed to an erythrocytic origin, since the resistant lines invade reticulocytes, which contain higher levels of GSH and GST than normocytes.

journal_name

Mol Biochem Parasitol

authors

Platel DF,Mangou F,Tribouley-Duret J

doi

10.1016/s0166-6851(98)00170-4

subject

Has Abstract

pub_date

1999-01-25 00:00:00

pages

215-23

issue

2

eissn

0166-6851

issn

1872-9428

pii

S0166685198001704

journal_volume

98

pub_type

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