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)

Antibody formation, endotoxin sensitivity, and resistance to a challenge malarial infection were evaluated in mice fed a diet containing polychlorinated biphenyl (PCB) (Aroclor 1242) or hexachlorobenzene (HCB). Antibody synthesis to the antigen sheep RBC (SRBC) was significantly depressed in the PCB- and HCB-treated (167 ppm) animals as evidenced by the fact that control mice elicited an approximate twofold increase in antibody formation over the chemical-treated mice. Serum IgA concentrations in the PCB- and HCB-treated mice were consistently 40--80 mg/dl lower than control values. Gram-negative endotoxin (Salmonella typhosa) sensitivity in PCB- and HCB-treated mice was increased 5.2- and 32-fold, respectively, following the dietary administration of 167 ppm of Aroclor 1242 or HCB for 6 weeks. An endotoxin hypersusceptibility was also noted at 3 weeks after dietary administration. Decreased resistance to a malaria challenge was also demonstrated in the xenobiotic-treated mice. A 20% decrease in mean survival time of mice fed Aroclor 1242 for 3 to 6 weeks and inoculated with Plasmodium berghei (NYU-2) was observed. Infected mice which had received HCB for 3 or 6 weeks manifested reductions in mean survival time of 24 and 31%, respectively. The data indicated that environmental chemical contaminants impair host resistance and, since no concomitant histopathological alterations were observed in the treated mice, the evaluation of immune parameters may possibly be a sensitive indicator of toxicity.
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PMID:Environmental chemical-induced immune dysfunction. 10 6

What have we learned? Pharmacogenetics, heritable variation in response to xenobiotics, is present in all forms of life. Initially, human data perhaps have created the most excitement, and they provide much biochemical detail. However, if we look at pharmacogenetic variation of insects and bacteria, we see it as a characteristic of populations; individuals with inborn resistance to various toxicants can cause the survival of a population by the process of Darwinian selection. Diversity of a population and Darwinian selection are different milestones serving population survival. Variation of drug response may represent variation of drug targets, drug metabolism, and probably drug transport. Metabolic variation appears to be the most prominent; at present, it is not clear whether this prominence has historical or biological causes. It is an interesting exercise to compare pharmacogenetic resistance with intoxication and resistance to infection by invasion of disease-carrying bacteria or other pathogens. The big difference is that pathogens tend to show variabilities that drugs do not have. The immune system is made to deal with the genetic variabilities linked to the short life span of most pathogens. However, there are, besides the immune system, several cases of genetic host resistance associated with the long life span of mammalian hosts. Such genetic host resistances are factors equivalent to pharmacogenetic variation. Current data pertain to resistance against malaria, tuberculosis, cholera, and AIDS. Most pharmacogenetic variants within a population are preadaptive, that is, they are established before xenobiotic exposure. Hence, one must postulate a multiplicity of variants in a population capable of resisting a multiplicity of drugs. The persistence of this multiplicity suggests that most variants are either present in heterozygous form and are thereby advantageous for their carriers, or they are selectively neutral mutants. It means that the biological cost of pharmacogenetic diversity, measured in terms of reduced fertility, should be low in a population. The frequencies of variant genes are usually not the same in different populations. Also the nucleotide substitutions in a variable gene often differ between populations. In other words, pharmacogenetic differences between populations are typical events. Pharmacogenetics is usually thought of as the study of a situation in which a single gene product exerts control over a given drug response so that a failure to respond, or an excessive response, may result. However, one should not forget that random variation is always present, probably reflecting the randomness of mutations plus variation of any environmental factors that might contribute. This underlying randomness of variation will always affect the picture of any all-or-none variation. Future pharmacogenetics must deal with both random and monogenic variation.
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PMID:Pharmacogenetics in biological perspective. 944 63

Malaria remains the most prevalent infectious disease of tropical and subtropical areas of the world. It represents a crucial problem in public health care, affecting 750 million people annually, of whom at least two million die. Various antimalarials currently used were studied for their capability to induce expression of the cytochrome P450 1A1 (CYP1A1) gene, an enzyme that plays an important role in the activation of xenobiotics to genotoxic derivatives. Studies on human hepatocytes and HepG2 cell lines showed that primaquine was capable of dose dependently increasing both the ethoxyresorufin-O-deethylase activity and CYP1A1 mRNAs, suggesting a transcriptional activation of this gene. Moreover, alpha-naphthoflavone, a partial aryl hydrocarbon receptor (AhR) antagonist, and 8-methoxypsoralen, which interferes with the binding of activated AhR to the xenobiotic responsive element, were shown to suppress CYP1A1 induction when added to the cultures. However, neither primaquine nor its metabolites were able to displace [3H]2,3,7,8-tetrachlorodibenzo-p-dioxin from AhR in competitive binding studies using 9S-enriched fractions of human cytosol. These data, together with the induction of CYP1A1 promoter-directed chloramphenicol acetyl transferase gene expression, suggest that CYP1A1 induction involves the participation of the AhR but not a direct primaquine-receptor interaction. This supports the notion that an alternative ligand-independent mechanism has to be considered. Given the pharmaco-toxicological significance of CYP1A1 induction, these findings may have important implications in the treatment of malaria with primaquine and new analogs.
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PMID:Cytochrome 1A1 induction by primaquine in human hepatocytes and HepG2 cells: absence of binding to the aryl hydrocarbon receptor. 989 May 52

Cytochrome P450 2C19 (CYP2C19) is the main (or partial) cause for large differences in the pharmacokinetics of a number of clinically important drugs. On the basis of their ability to metabolise (S)-mephenytoin or other CYP2C19 substrates, individuals can be classified as extensive metabolisers (EMs) or poor metabolisers (PMs). Eight variant alleles (CYP2C19*2 to CYP2C19*8) that predict PMs have been identified. The distribution of EM and PM genotypes and phenotypes shows wide interethnic differences. Nongenetic factors such as enzyme inhibition and induction, old age and liver cirrhosis can also modulate CYP2C19 activity. In EMs, approximately 80% of doses of the proton pump inhibitors (PPIs) omeprazole, lansoprazole and pantoprazole seem to be cleared by CYP2C19, whereas CYP3A is more important in PMs. Five-fold higher exposure to these drugs is observed in PMs than in EMs of CYP2C19, and further increases occur during inhibition of CYP3A-catalysed alternative metabolic pathways in PMs. As a result, PMs of CYP2C19 experience more effective acid suppression and better healing of duodenal and gastric ulcers during treatment with omeprazole and lansoprazole compared with EMs. The pharmacoeconomic value of CYP2C19 genotyping remains unclear. Our calculations suggest that genotyping for CYP2C19 could save approximately 5000 US dollars for every 100 Asians tested, but none for Caucasian patients. Nevertheless, genotyping for the common alleles of CYP2C19 before initiating PPIs for the treatment of reflux disease and H. pylori infection is a cost effective tool to determine appropriate duration of treatment and dosage regimens. Altered CYP2C19 activity does not seem to increase the risk for adverse drug reactions/interactions of PPIs. Phenytoin plasma concentrations and toxicity have been shown to increase in patients taking inhibitors of CYP2C19 or who have variant alleles and, because of its narrow therapeutic range, genotyping of CYP2C19 in addition to CYP2C9 may be needed to optimise the dosage of phenytoin. Increased risk of toxicity of tricyclic antidepressants is likely in patients whose CYP2C19 and/or CYP2D6 activities are diminished. CYP2C19 is a major enzyme in proguanil activation to cycloguanil, but there are no clinical data that suggest that PMs of CYP2C19 are at a greater risk for failure of malaria prophylaxis or treatment. Diazepam clearance is clearly diminished in PMs or when inhibitors of CYP2C19 are coprescribed, but the clinical consequences are generally minimal. Finally, many studies have attempted to identify relationships between CYP2C19 genotype and phenotype and susceptibility to xenobiotic-induced disease, but none of these are compelling.
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PMID:Clinical significance of the cytochrome P450 2C19 genetic polymorphism. 1222 94

A microarray containing approximately 20 000 expressed sequence tags (ESTs; 11 760 unique EST clusters) from the malaria vector, Anopheles gambiae, was used to monitor differences in global gene expression in two insecticide resistant and one susceptible strains. Statistical analysis identified 77 ESTs that were differentially transcribed among the three strains. These include the cytochrome P450 CYP314A1, over-transcribed in the DDT resistant ZAN/U strain, and many genes that belong to families not usually associated with insecticide resistance, such as peptidases, sodium/calcium exchangers and genes implicated in lipid and carbohydrate metabolism. Short-term (6 and 10 h) effects of exposure of the pyrethroid resistant RSP strain to permethrin were also detected. Several genes belonging to enzyme families already implicated in insecticide or xenobiotic detoxification were induced, including the carboxylesterase COEAE2F gene and members of the UDP-glucuronosyl transferase and nitrilase families.
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PMID:Gene expression in insecticide resistant and susceptible Anopheles gambiae strains constitutively or after insecticide exposure. 1616 7

Glutathione S-transferases (GST) are a family of enzymes involved in phase-II detoxification of endogenous and xenobiotic compounds. Polymorphisms in GST genes have been associated with susceptibility to different diseases. In this study we determined the frequencies of polymorphisms in GSTM1, GSTT1, and GSTP1 in DNA of 138 children from Cameroon, presenting with uncomplicated malaria (N = 19), malaria with minor complications (N = 81), or severe malaria (N = 38). Analyses of GSTM1 and GSTT1 were performed using PCR-multiplex procedure, while GSTP1 was done by PCR-RFLP. Subjects presenting with malaria with complications were found more often of the GSTM1-null genotype (58-64%) as compared with those with uncomplicated malaria (32%), a difference that was statistically significant. We conclude that the GSTM1-null genotype is associated with malaria with complications.
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PMID:Short report: Severe Plasmodium falciparum malaria in Cameroon: associated with the glutathione S-transferase M1 null genotype. 1712 72

Annotation of the recently determined genome sequence of the major dengue vector, Aedes aegypti, reveals an abundance of detoxification genes. Here, we report the presence of 235 members of the cytochrome P450, glutathione transferase and carboxy/cholinesterase families in Ae. aegypti. This gene count represents an increase of 58% and 36% compared with the fruitfly, Drosophila melanogaster, and the malaria mosquito, Anopheles gambiae, respectively. The expansion is not uniform within the gene families. Secure orthologs can be found across the insect species for enzymes that have presumed or proven biosynthetic or housekeeping roles. In contrast, subsets of these gene families that are associated with general xenobiotic detoxification, in particular the CYP6, CYP9 and alpha esterase families, have expanded in Ae. aegypti. In order to identify detoxification genes associated with resistance to insecticides we constructed an array containing unique oligonucleotide probes for these genes and compared their expression level in insecticide resistant and susceptible strains. Several candidate genes were identified with the majority belonging to two gene families, the CYP9 P450s and the Epsilon GSTs. This 'Ae. aegypti Detox Chip' will facilitate the implementation of insecticide resistance management strategies for arboviral control programmes.
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PMID:Genomic analysis of detoxification genes in the mosquito Aedes aegypti. 1807 Jun 70

Glutathione S transferases (GSTs) are multifunctional enzymes involved in detoxification of xenobiotic compounds in majority of the insect groups. Significance of insect GSTs is their elevated level of activity in association with insecticide resistance. This investigation was to explore the metabolic status of GSTs in two Indian DDT-resistant malaria vectors, Anopheles culicifacies and Anopheles annularis, and one DDT-susceptible vector, Anopheles fluviatilis. Malkangiri and Koraput districts of Orissa State, endemic for falciparum malaria and having a long insecticide spraying history, were the study areas. F1 progeny was raised from wild-caught females of the three vectors and used for biochemical assays to detect the GST-mediated DDT resistance mechanism. Results of the enzyme assay showed a significant 3-fold increase in GST activity in DDT-resistant An. annularis compared with its susceptible population. In DDT-resistant An. culicifacies, the median GST activity (71.8 micromol/min/mg) was almost the same as estimated in the DDT-resistant An. annularis (74.6 micromol/ min/mg), suggesting that the GST activity estimated in An. culicifacies could be an elevated level for detoxification of DDT. Furthermore, the GST activity in DDT-resistant An. culicifacies and An. annularis was significantly higher than that in the DDT-susceptible An. fluviatilis, which had a GST activity of 20.0 micromol/min/mg. Also, the GST-mediated DDT detoxification was confirmed by comparing GST activity in wild-caught females with that in their F1 progeny.
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PMID:Glutathione S transferase activity in Indian vectors of malaria: A defense mechanism against DDT. 2166 17

Medicinal plants are a rich source of biologically-active phytochemicals and have been used in traditional medicine for centuries. Specific phytochemicals and extracts of their plant sources have the ability to reduce the risk for chronic degenerative diseases by induction of enzymes involved in xenobiotic metabolism, many of which also have antioxidant and anti-inflammatory functions. One such multifunctional cytoprotective enzyme is NAD(P)H : quinone oxidoreductase. In this study, we prepared extracts of 27 Saudi Arabian medicinal plants which belong to 18 different plant families and tested their ability to induce NAD(P)H : quinone oxidoreductase in murine hepatoma cells grown in microtiter plate wells. In addition to the Brassicaceae, a known source of NAD(P)H : quinone oxidoreductase inducer activity, we found substantial inducer activity in extracts from the Apiaceae, Apocynaceae, and the Asteraceae families. Five out of a total of eight active extracts are from plants which belong to the Asteraceae family. We further show that artemisinin, an agent which is used clinically for the treatment of malaria, contributes but does not fully account for the inducer activity of the extract of Artemisia monosperma. In contrast to artemisinin, deoxyartemisinin is inactive in this assay, demonstrating the critical role of the endoperoxide moiety of artemisinin for inducer activity. Thus, the NAD(P)H : quinone oxidoreductase inducer activity of extracts of some Saudi Arabian medicinal plants indicates the presence of specific phytochemicals which have the potential to protect against chronic degenerative diseases.
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PMID:NAD(P)H : quinone oxidoreductase 1 inducer activity of some Saudi Arabian medicinal plants. 2351 1

The cytochrome P450 monooxygenase (P450) enzyme system is a major mechanism of xenobiotic biotransformation. The nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome P450 reductase (CPR) is required for transfer of electrons from NADPH to P450. One CPR gene was identified in the genome of the malaria-transmitting mosquito Anopheles stephensi Liston (Diptera: Culicidae). The gene encodes a polypeptide containing highly conserved flavin mononucleotide-, flavin adenine dinucleotide-, and NADPH-binding domains, a unique characteristic of the reductase. Phylogenetic analysis revealed that the A. stephensi and other known mosquito CPRs belong to a monophyletic group distinctly separated from other insects in the same order, Diptera. Amino acid residues of CPRs involved in binding of P450 and cytochrome c are conserved between A. stephensi and the Norway rat Rattus norvegicus Berkenhout (Rodentia: Muridae). However, gene structure particularly within the coding region is evidently different between the two organisms. Such difference might arise during the evolution process as also seen in the difference of P450 families and isoforms found in these organisms. CPR in the mosquito A. stephensi is expected to be active and serve as an essential component of the P450 system.
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PMID:Genomic and bioinformatic analysis of NADPH-cytochrome P450 reductase in Anopheles stephensi (Diptera: Culicidae). 2536 81


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