The role of cytochrome P450 and P-glycoprotein in the development of resistance by Plasmodium falciparum to chloroquine
1. Drug resistant strains of P. falciparum are becoming increasingly prevalent in most malaria endemic areas of the world, complicating treatment and prophylaxis. The prevalence of P. falciparum was assessed in six villages in the Punjab, Pakistan. The study was carried out during the months of August-October, 1992. A total of 566 people was surveyed. Fifty blood samples from positive plasmodial cases were analysed. Overall P. falciparum comprised the highest proportion of cases (62.39%) followed by P. vivax (36.7%) and mixed infection (0.85%) and mixed infection (0.85%). The slide positivity rate was 20.6%. The prevalence rate of plasmodial infection in the combined population was 3.8/1000. This is higher than the reported national prevalence rate of 0.7/1000 (WHO, 1992). 2. Sensitivity to chloroquine of the cultured isolates was carried out by [3H]hypoxanthine incorporation and by microscopical assessment. 3. In mammalian cells mixed function oxidase systems of which cytochrome P450 is the terminal oxidase are responsible for the metabolism of a whole variety of structurally unrelated xenobiotics, which include antimalarial drugs. 4. An alternative method of resistance was investigated by examining the relationship between resistance and chloroquine accumulation and efflux in P. falciparum using [3H]chloroquine. 5. Verapamil, a calcium channel blocker has been shown to reverse completely chloroquine-resistance in chloroquine-resistant P. falciparum isolates. 6. The digestive vacuole is thought to be the site of action of chloroquine on the malarial parasite. 7. The ultimate target of chloroquine and related drugs remains unclear. Drug resistance may be a result of decreased vacuolar accumulation in chloroquine-resistant parasites.