| Co-Investigator(Kenkyū-buntansha) |
TSUKAHARA Takahiro Department. of International Affairs and Tropical Medicine. Tokyo Women's Medical University School of Medicine Research Fellow, 医学部, 助手 (90328378)
TAKAGI Masahiro Institute of Tropical Medicine, Nagasaki University Professor, 熱帯医学研究所, 教授 (60024684)
ISHIZAKI Tkashi Department of Clinical Pharmacology and Therapeutics, Kumamoto University Professor, 大学院・臨床薬学薬物治療講座, 教授 (50158747)
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| Research Abstract |
The genetic diversities displayed by human and malaria parasites at different frequencies in different geographical areas represent a major obstacle for the development of malaria control strategies including malaria chemotherapy and malaria vaccine. We investigated some genetic diversities on Vanuatu islands with various malaria endemicities. Malaria in Vanuatu is unstable, mainly hypo-to mesoendemic and seasonal with occasional epidemics.
The frequencies of the cytochrome P450 (CYP) 2C19 mutant alleles were uniformly greater in Vanuatu. However there were differences between populations from different islands. Comparisons of genetic, linguistic and geographic patterns suggested that short range gene flow is largely responsible for the current distribution of CYP2C19alleles in Vanuatu. Our data in malaria patients demonstrated an association between CYP2C19 mutations and poor metabolism of proguanil to cycloguanil, a strong dihydrofolate reductase (DHFR) inhibitor, and an apparent gene
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dose effect relationship.
Restricted diversity in the dhfr gene was shown in a total of 140 P.falciparunm cases on isolated islands of Vanuatu. All isolates had the same Asn- 108 mutation, and all, except in Gaua, also had Arg-59 mutation, normally associated with moderate resistance to DHFR-inhibiting drugs. The 3 remaining isolates in Gaua had His-51, a change not previously reported in the literature. Despite these partly resistant variants, pyrimethamine and sulfadoxine treatment was still highly effective. The restricted diversity of the dhfr gene in unstable malaria endemicity on Vanuatu islands may be at least partly explained by a loss in heterozygosity of the parasite populations derived from periodically interrupted transmission and isolation with limited gene flows between islands.
Mutations in human CYP2C19 and parasite dhfr genes, related to poor metabolism of proguanil and resistance to cycloguanil respectively, have both been assumed to be associated with poor antimalarial effect by proguanil. We however observed high antimalarial efficacy of proguanil also in patients with CYP2C19 related poor metabolize genotype and the common dhfr genotype (Arg-59 and Asn-108). This suggested that the parent compound proguanil has an intrinsic efficacy independent of the metabolite cycloguanil and the dhfr mutation.
The frequencies of the cytochrome P450 (CYP) 2C19 mutant alleles were uniformly greater in Vanuatu. However there were differences between populations from different islands. Comparisons of genetic, linguistic and geographic patterns suggested that short range gene flow is largely responsible for the current distribution of CYP2C19alleles in Vanuatu. Our data in malaria patients demonstrated an association between CYP2C19 mutations and poor metabolism of proguanil to cycloguanil, a strong dihydrofolate reductase (DHFR) inhibitor, and an apparent gene dose effect relationship. Less
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