Molecular-dynamic correlates of oxidant haemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficiency

Project Overview

Global distribution of G6PD variants

Glucose -6-phosphate dehydrogenase (G6PD) deficiency, the most common human enzyme deficiency (>180 different genotypes), affects approximately 400 million people worldwide (Beutler, 2008). Deficiency reduces production of NADPH, and lowers intraerythrocytic stores of reduced glutathione – a major defence against oxidant damage. Oxidant drugs and foods cause haemolysis in G6PD deficiency, which can be severe. Enzyme deficiency protects against severe malaria and so the abnormality is prevalent mainly in areas where malaria is or was prevalent. Most studies have been performed in patients with the African A- genotype. Dose-response (haemolysis) relationships, and thus the therapeutic ratio in patients with other G6PD deficiency genotypes are much less well characterised. In most G6PD deficiency variants there is instability of the mutant enzyme which is degraded more rapidly than the normal enzyme. Older red cells are relatively G6PD depleted and haemolyse preferentially. As there is some enzyme activity, and therefore some oxidant defence, in the younger erythrocytes red cell destruction does not usually begin immediately on exposure to oxidant stress, and is self limiting G6PD deficiency is sex linked so hemizygous males and homozygous females are affected. Variable X-inactivation (Lyonisation), means that heterozygote females are chimaeras and so they are also partially affected. Heterozygote females very rarely develop severe haemolysis. Oxidant haemolysis is a major obstacle to the deployment of primaquine (Baird & Rieckmann, 2003) – the only available drug for the radical treatment of vivax malaria.

Plan of investigation: This project will be based in the Mahidol-Oxford Tropical Medicine Research Unit in Bangkok, Thailand (G6PD gene frequency circa 10-15%). The pharmacokinetic (plasma primaquine and metabolites)-pharmacodynamic (red cell survival and differential haemolysis) relationships in primaquine haemolysis (Houston, 1997) will be characterized in hemizygote females and homozygote males. Evidence on safety and haemolysis from large clinical trials will be gathered. This will facilitate evidence-based recommendations on primaquine deployment.

Training Opportunities

The project will include training in clinical investigation, clinical malariology, haematological assessment, PCR genotyping, antimalarial drug measurement, PK-PD modeling, and statistical analysis. In the Oxford Unit based in Thailand there is a large, vibrant, multidisciplinary grouping of scientists and clinicians dedicated to the study of clinically important tropical infections, and the fellow would become part of this Unit. The Unit has weekly scientific meetings at which the fellow would be expected to attend and to present their findings.

Theme

Tropical Medicine & Global Health and Physiology, Cellular & Molecular Biology

Admissions

Project reference number: 126

Funding and admissions information

Supervisors

Name Department Institution Country Email
Prof Nicholas J White FRS Tropical Medicine Oxford University UK nickw@tropmedres.ac
Prof Nicholas PJ Day FMedSci FRCP Tropical Medicine Oxford University UK nickd@tropmedres.ac
Prof François H Nosten Tropical Medicine Oxford University UK francois@tropmedres.ac
Prof Sir David Weatherall KBE FRS FMedSci Nuffield Division of Clinical Laboratory Sciences Oxford University UK david.weatherall@imm.ox.ac.uk

Beutler E. 2008. Glucose-6-phosphate dehydrogenase deficiency: a historical perspective. Blood, 111 (1), pp. 16-24. Read abstract | Read more

Glucose-6-phosphate dehydrogenase deficiency serves as a prototype of the many human enzyme deficiencies that are now known. Since its discovery more than 50 years ago, the high prevalence of the defect and the easy accessibility of the cells that manifest it have made it a favorite tool of biochemists, epidemiologists, geneticists, and molecular biologists as well as clinicians. In this brief historical review, we trace the discovery of this defect, its clinical manifestations, detection, population genetics, and molecular biology. Hide abstract

Baird JK, Rieckmann KH. 2003. Can primaquine therapy for vivax malaria be improved? Trends Parasitol., 19 (3), pp. 115-20. Read abstract | Read more

The incidence and range of endemic malaria caused by Plasmodium vivax has expanded during the past 30 years. This parasite forms hypnozoites in the liver, creating a persistent reservoir of infection. Primaquine (PQ), introduced 50 years ago, is the only drug available to eliminate hypnozoites. However, lengthy treatment courses and follow-up periods are not conducive to assessing the effectiveness of this drug in preventing relapses. Resistance to standard therapy could be widespread. Studies are urgently needed to gauge this problem and to determine the safety, tolerability and efficacy of shorter courses and higher doses of PQ. Hide abstract

Houston S. 1997. The role of glucose-6-phosphate dehydrogenase deficiency in blackwater fever. Clin. Infect. Dis., 25 (5), pp. 1275. | Read more