Breakthrough in combating the side effects of quinine

Discovered back in the 1600s quinine was the first effective treatment in the fight against malaria – and it continues to be a commonly used treatment against this devastating disease. But the drug is associated with a long list of side effects which can range from sickness and headaches to blindness, deafness and in rare cases death — and until now no one knew why. Scientists at The University of Nottingham have made a discovery that may explain many of the adverse side-effects associated with the drug and as a result have potentially found a way of combating them.

Their research, funded by The Sir Halley Stewart Trust, found that quinine can block a cell's ability to take up the essential amino acid tryptophan. The findings, published today in the Journal of Biological Chemistry, suggest that dietary tryptophan supplements could be a cheap and simple way to improve the performance of this important drug.

Dr Simon Avery and colleagues in the School of Biology used yeast genetics to examine the effects of quinine on a collection of 6000 yeast mutants, each one lacking exactly one of the yeast's 6000 genes. While quite different from humans, yeast is comparable on a cellular level and yeast is frequently, and successfully, used as a front-line agent in testing chemicals and small molecule drugs.

This detailed screening process revealed that strains of yeast unable to make tryptophan were extremely susceptible to quinine poisoning, which led them to identify a tryptophan transporter as a key quinine target (yeast that cannot make their own tryptophan have to rely exclusively on external sources, and thus die if tryptophan transport is blocked).

This discovery fits in well with evidence that quinine reactions are more severe in malnourished individuals. Tryptophan is an essential amino acid which means the human body cannot produce it — we have to get it from the food we eat. Tryptophan is abundant in meat but limited in yams, a staple food crop in the tropics where malaria is prevalent. If quinine severely reduces tryptophan uptake, then it follows that people with preexisting tryptophan deficiency, a common occurrence in undernourished populations, would be especially at risk from this drug.

Each year there are an estimated 350 to 500 million cases of malaria — and every year it kills between one and three million people. In Africa, malaria is a leading cause of death in children. Estimates are that worldwide over three billion people are at risk of contracting the disease.

Dr Simon Avery said: "This finding could be a key step towards making quinine side-effects a thing of the past, so improving the quality of treatment for millions of malaria sufferers. It also highlights the benefits of collaborative research, in this case between my yeast group and the parasite immunology group of Dr. Richard Pleass."

The body uses tryptophan to make the brain chemical serotonin — which is thought to produce healthy sleep and a stable mood - so a lack of tryptophan induced by quinine could also explain why many of quinine's side effects are localized to the head region.

The researchers postulate that the toxic effects of quinine could be averted simply by taking dietary tryptophan supplements in conjunction with quinine treatments. Scientists now have to find out if tryptophan affects quinine action against the malaria parasite.

Source: University of Nottingham