Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Degenerate oligonucleotide primers were designed for conserved regions of cytochrome P450 proteins of the CYP4 family and were used to amplify cDNA or genomic DNA from different strains of the New World malaria vector, Anopheles albimanus (Weidemann). The PCR products were cloned, sequenced and compared to each other and to members of the P450 family CYP4. Seventeen new P450 genes were identified in five CYP4 subfamilies. Five of the ten PCR products of genomic DNA were shown to contain a short (60-79 bp) intron at the same position as introns in the Drosophila CYP4D2 and CYP4E1 genes.
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PMID:Diversity of cytochrome P450 genes in the mosquito, Anopheles albimanus. 754 68

Antipyrine and metronidazole were administered as a cocktail to young (4 weeks old) male Wistar rats (N = 12 for each treatment) to investigate the effect of malaria infection due to the rodent parasite Plasmodium berghei and Escherichia coli endotoxin-induced fever on the metabolism of the two compounds in vivo. Control rats received normal saline. Antipyrine and metronidazole clearances were estimated from a single saliva sample while the formation clearances of their metabolites (in malaria-infected and control rats) were estimated from the product of clearance of parent drug and the fraction of the administered dose excreted as metabolites in urine in 24 hr. Rats treated with endotoxin produced no urine during this period. Malaria infection had no effect on clearance of antipyrine or on formation clearance of any of its metabolites. However, the clearance of metronidazole was reduced by approximately 20% compared with controls as a result of decreased formation of hydroxymetronidazole. Fever decreased clearance of both antipyrine and metronidazole by approximately 36% and 23%, respectively. These results demonstrate that both malaria infection and fever can influence P450-dependent drug metabolism and the effects seen appear to be isozyme-selective.
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PMID:Effect of malaria infection and endotoxin-induced fever on the metabolism of antipyrine and metronidazole in the rat. 846 45

1. Artelinic acid (AL), a water-soluble artemisinin analogue for treatment of multidrug resistant malaria, is metabolized to the active metabolite dihydroqinghaosu (DQHS) solely by CYP3A4/5. Although AL is not metabolized by CYP2C9, it does inhibit diclofenac 4-hydroxylase activity with an IC50 = 115 microM. Interestingly, AL activates CYP2D6-mediated bufuralol metabolism in human liver microsomes but not recombinant CYP2D6-Val by approximately 30% at AL concentrations up to 100 microM. 2. In human liver microsomes, AL is metabolized to DQHS with a Km = 157 +/- 44 microM and Vmax = 0.77 +/- 0.56 nmol DQHS/min/mg protein. Human recombinant CYP3A4 catalysed the conversion of AL to DQHS with a Km = 102 +/- 23 microM and a Vmax = 1.96 +/- 0.38 nmol DQHS/min/nmol P450. The kinetic parameters (Km and Vmax) for DQHS formation from CYP3A5 were 189 +/- 19 microM and 3.60 +/- 0.42 nmol DQHS/min/nmol P450 respectively. 3. Inhibition studies suggest that azole antifungals and calcium channel blockers may present clinically significant drug drug interactions. In human liver microsomes, ketoconazole and miconazole were potent competitive inhibitors of DQHS formation with a Ki = 0.028 and 0.124 microM respectively. Verapamil is a non-competitive inhibitor of DQHS formation in human liver microsomes with a Ki = 15 microM.
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PMID:Metabolism of artelinic acid to dihydroqinqhaosu by human liver cytochrome P4503A. 1045 89

The aim of this study was to elucidate the metabolic pathways for dihydroartemisinin (DHA), the active metabolite of the artemisinin derivative artesunate (ARTS). Urine was collected from 17 Vietnamese adults with falciparum malaria who had received 120 mg of ARTS i.v., and metabolites were analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS). Human liver microsomes were incubated with [12-(3)H]DHA and cofactors for either glucuronidation or cytochrome P450-catalyzed oxidation. Human liver cytosol was incubated with cofactor for sulfation. Metabolites were detected by HPLC-MS and/or HPLC with radiochemical detection. Metabolism of DHA by recombinant human UDP-glucuronosyltransferases (UGTs) was studied. HPLC-MS analysis of urine identified alpha-DHA-beta-glucuronide (alpha-DHA-G) and a product characterized as the tetrahydrofuran isomer of alpha-DHA-G. DHA was present only in very small amounts. The ratio of the tetrahydrofuran isomer, alpha-DHA-G, was highly variable (median 0.75; range 0.09-64). Nevertheless, alpha-DHA-G was generally the major urinary product of DHA glucuronidation in patients. The tetrahydrofuran isomer appeared to be at least partly a product of nonenzymic reactions occurring in urine and was readily formed from alpha-DHA-G by iron-mediated isomerization. In human liver microsomal incubations, DHA-G (diastereomer unspecified) was the only metabolite found (V(max) 177 +/- 47 pmol min(-1) mg(-1), K(m) 90 +/- 16 microM). Alpha-DHA-G was formed in incubations of DHA with expressed UGT1A9 (K(m) 32 microM, V(max) 8.9 pmol min(-1) mg(-1)) or UGT2B7 (K(m) 438 microM, V(max) 10.9 pmol mg(-1) min(-1)) but not with UGT1A1 or UGT1A6. There was no significant metabolism of DHA by cytochrome-P450 oxidation or by cytosolic sulfotransferases. We conclude that alpha-DHA-G is an important metabolite of DHA in humans and that its formation is catalyzed by UGT1A9 and UGT2B7.
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PMID:Glucuronidation of dihydroartemisinin in vivo and by human liver microsomes and expressed UDP-glucuronosyltransferases. 1216 66

Cytochrome P450s are a superfamily of haemoproteins, important in the metabolism of endogenous compounds and xenobiotics. As a first step to elucidating the role of this family in insecticide resistance in the malaria mosquito, Anopheles gambiae, we have cloned and mapped multiple P450 genes. Sixteen cDNAs encoding full-length P450s were cloned and physically mapped to the mosquito's polytene chromosomes. Fourteen of these encode putative CYP6 proteins and two encode P450s belonging to the CYP9 class. Eighteen new A. gambiae Cyp4 P450 genes were identified using degenerate PCR primers, cDNAs were detected for ten and in situ locations for thirteen members of this gene family.
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PMID:Molecular analysis of multiple cytochrome P450 genes from the malaria vector, Anopheles gambiae. 1223 May 40

Many malaria control programmes are based on insecticide application as adulticides, often in the form of pyrethroid-impregnated bed nets. However, the efficacy of this control measure can be reduced by genetic changes in vector insecticide susceptibility. Pyrethroid resistance has been detected in the major African malaria vector, Anopheles gambiae, and has been attributed to a combination of target site insensitivity and increased oxidative metabolism of the insecticide, catalysed by cytochrome P450s. An adult-specific cytochrome P450 monooxygenase 6 (CYP6) P450 gene, CYP6Z1, located within a large cluster of cytochrome P450 genes in chromosome arm 3R of An. gambiae, is expressed approximately 11-fold higher in males and 4.5-fold in females from a pyrethroid-resistant strain than in a susceptible strain from the same geographical area. In both strains, CYP6Z1 expression is higher in males than females. Southern blot analysis discounted gene amplification as a cause of this overexpression. The isolation of An. gambiae cDNAs encoding cytochrome b(5) and nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH)-cytochrome P450 reductase cDNAs is also reported.
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PMID:An adult-specific CYP6 P450 gene is overexpressed in a pyrethroid-resistant strain of the malaria vector, Anopheles gambiae. 1458 2

Two new genes in the cytochrome P450 (CYP6) family 6 with complete coding sequences were cloned and sequenced from deltamethrin-resistant Anopheles minimus, a major malaria vector in Thailand. CYP6P5 encodes a protein of 508 amino acids, while CYP6AA2 contains 505 residues. Each encoded protein contains a hydrophobic N-terminal region and a highly conserved heme-binding region typical of P450s. Alignments of deduced amino acid sequences with other insect P450 genes indicate a high degree of identity to insect CYP6 genes. Comparative mRNA expression studies using semi-quantitative RT-PCR analysis indicated that the relative amount of CYP6AA2 transcript was greater in the deltamethrin-resistant An. minimus compared to the susceptible strain. The expression of CYP6AA2 in deltamethrin-resistant mosquitoes is associated with development of deltamethrin resistance in An. minimus mosquito. The CYP6P5 transcript is equally expressed in both resistant and susceptible mosquitoes.
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PMID:Cloning of cytochrome P450, CYP6P5, and CYP6AA2 from Anopheles minimus resistant to deltamethrin. 1471 62

Metabolic pathways play an important role in insecticide resistance, but the full spectra of the genes involved in resistance has not been established. We constructed a microarray containing unique fragments from 230 Anopheles gambiae genes putatively involved in insecticide metabolism [cytochrome P450s (P450s), GSTs, and carboxylesterases and redox genes, partners of the P450 oxidative metabolic complex, and various controls]. We used this detox chip to monitor the expression of the detoxifying genes in insecticide resistant and susceptible An. gambiae laboratory strains. Five genes were strongly up-regulated in the dichlorodiphenyltrichloroethane-resistant strain ZAN/U. These genes included the GST GSTE2, which has previously been implicated in dichlorodiphenyltrichloroethane resistance, two P450s, and two peroxidase genes. GSTE2 was also elevated in the pyrethroid-resistant RSP strain. In addition, the P450 CYP325A3, belonging to a class not previously associated with insecticide resistance, was expressed at statistically higher levels in this strain. The applications of this detox chip and its potential contribution to malaria vector insecticide resistance management programs are discussed.
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PMID:The Anopheles gambiae detoxification chip: a highly specific microarray to study metabolic-based insecticide resistance in malaria vectors. 1575 17

Anopheles gambiae Giles s.s. (Diptera: Culicidae) is one of the principal vectors of malaria in the Ashanti region of central Ghana. High levels of resistance to dieldrin were recorded in a wild-caught sample from Obuasi (south of Kumasi) as well as a laboratory colony established using material from the wild population. Cytogenetic analysis of wild-caught and laboratory samples revealed chromosomal polymorphism for inversions 2La and 2Rb. Although inversion 2La has previously been shown to be associated with dieldrin resistance in certain other laboratory strains originating from West Africa, there was no obvious association between inversion karyotype assortment and the resistance phenotype in the Obuasi population. In addition, polymerase chain reaction analysis indicated the presence of the alanine296 to glycine mutation in the GABA (gamma amino-butyric acid) receptor (which has been mapped to a chromosomal position within inversion 2La). This mutation has previously been shown to be associated with dieldrin resistance in the same An. gambiae laboratory strains of West African origin. Our data show only a weak association between the dieldrin resistance phenotype and the presence of this mutation, suggesting that another dieldrin resistance mechanism is operational in the Obuasi population. Biochemical and synergist exposure assays suggest a metabolic component, probably mediated by monooxygenase P450 enzymes. We conclude that dieldrin resistance in the An. gambiae population of the Obuasi region occurs at a high level - most likely in the absence of selection - and that control of the resistance phenotype is polyfactorial and must include components other than mutations in the GABA receptor locus.
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PMID:Dieldrin resistance in the malaria vector Anopheles gambiae in Ghana. 1704 80

Malaria has been reported to modulate the activity of cytochrome-P450 enzymes (CYP). Since CYPs are involved both in the activation and detoxication of xenobiotics, we investigated whether malaria would modify the effects of chemical carcinogens in the bone-marrow micronucleus assay. Female C57BL6 mice were infected with Plasmodium berghei (ANKA) and treated (ip route) with cyclophosphamide (CPA, 25 mg/kg body weight), 7,12-dimethylbenz[a]anthracene (DMBA, 50mg/kg body weight) or ethyl methanesulfonate (EMS, 150 mg/kg body weight), on post-infection days 9-12 when parasitemia was > or =9% of RBC. Controls were age-paired non-infected mice. Bone marrows were sampled at 24 and 48 h (CPA), 24 h (EMS) or 48 h (DMBA) after treatment. The background incidence of polychromatic erythrocytes with micronuclei (MN-PCE) in malaria-infected mice was approximately twofold the background incidence in non-infected controls. Effects of indirect clastogens (CPA and DMBA) in the micronucleus assay were attenuated while the effect of EMS, a direct clastogen, was enhanced by infection. In a separate experiment, malaria was shown to decrease activities of ethoxy-(EROD, a marker for CYP1A) and benzyloxy-(BROD, CYP2B) resorufin-O-dealkylases in liver microsomes. The foregoing findings are consistent with the hypothesis that malaria-caused attenuation of genotoxicity arose from a down modulation of CYP isoforms that convert CPA (CYP2B) and DMBA (CYP1A) into their active metabolites.
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PMID:Malaria infection modulates effects of genotoxic chemicals in the mouse bone-marrow micronucleus test. 1785 Nov 16


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