Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Resistance of Plasmodium falciparum to many therapeutic agents is an increasing problem in most endemic areas. The role of the mdr-like gene products of P. falciparum in resistance to quinoline-containing compounds is not clear. The purpose of this study was to further examine the role of pfmdr1 in drug resistance in fresh clinical isolates originating from Africa. Drug susceptibility testing (chloroquine, mefloquine, halofantrine and quinine) and a molecular analysis of pfmdr1 was completed for 51 fresh clinical isolates. A statistical association between the chloroquine sensitivity phenotype and an intragenic allele of pfmdr1 was noted at a position, amino acid 86, which was previously associated with chloroquine resistance. There was little variation in the other intragenic alleles previously associated with chloroquine resistance. No correlation between pfmdr1 intragenic allelic variation and susceptibility to mefloquine, halofantrine or quinine was found. There was no association between gene copy number of pfmdr1 and any drug resistant phenotype in an analysis of selected isolates. This, along with other data, suggests that mefloquine resistance may have arisen by two different mechanisms in African and Southeast Asian isolates. Much more variability in the polyasparaginated region of the pfmdr1 gene was noted in this study than previously reported. In addition, fingerprint analysis using multiplex PCR revealed considerable genetic variability among these isolates.
Mol Biochem Parasitol 1995 Nov
PMID:Analysis of pfmdr1 and drug susceptibility in fresh isolates of Plasmodium falciparum from subsaharan Africa. 871 57

Recent investigations into quinoline and phenanthrene methanol resistance in Plasmodium falciparum have described a linkage between amplification of the mdr homologue pfmdr1 and decreased susceptibility to mefloquine (MQ) and halofantrine (HF). We have examined the current theories on cross-resistance patterns and pfmdr1 gene expression by comparing the chloroquine (CQ) resistant isolate K1 with K1Hf, developed from the K1 isolate by intermittent exposure to halofantrine. Reduced halofantrine susceptibility in K1Hf was accompanied by reduced sensitivity to mefloquine and increased sensitivity to chloroquine. These sensitivity changes were reflected by changes in parasite drug accumulation. The loss of high level chloroquine resistance in K1Hf was associated with an inability of verapamil to enhance chloroquine sensitivity or accumulation. In contrast verapamil retained the chemosensitising potential against quinine in this isolate. The changes in phenotype were achieved without any amplification or increased expression of pfmdr1 or reversion of the Tyr86 mutation in the gene. Our data indicates that acquisition of halofantrine and mefloquine resistance and the loss of high level chloroquine resistance can be achieved without enhanced expression of the pfmdr1 gene product.
Mol Biochem Parasitol 1996 Dec 02
PMID:In vitro selection of halofantrine resistance in Plasmodium falciparum is not associated with increased expression of Pgh1. 901 Aug 40

The DNA minor groove binders netropsin, distamycin and four structurally related bisquaternary ammonium heterocycles (BQA), SN 6999, SN 6570, SN 6132 and SN 6131, were investigated for sequence-specific interactions with the 154 base pair fragment of cDNA of the human Tau 40 protein (h Tau 40 protein), involved in pathology of Alzheimer's disease. The base sequences 5' AATCTT 3', 5' AATATT 3' and 5' TTTCAATCTTTTTATTT 3' were identified as ligand specific binding sites and demonstrate the obvious dA.dT binding preference. Footprinting titration experiments were performed to estimate sequence-specific binding constants (KA). The KA-values were in the order of 10(6)M-1 and dependent on DNA base sequence as well as ligands used. The highest values estimated were for netropsin (KA = 5.0 x 10(6)M-1) and the quinoline derivative SN 6999 (KA = 6.2 x 10(6)M-1) binding to the sequence 5' ATAAT 3'. Microscopic binding constants are determined by the base sequence rather than by the length of dA.dT stretches. In the extended dA.dT run, 5' TTTCAATCTTTTTATTT 3', netropsin and distamycin binding tolerates the presence of two dG.dC base pairs, as indicated by nearly unaffected footprints. In contrast, the failure of BQAs to form footprints demonstrates their significantly decreased binding selectivity.
Biochem Mol Biol Int 1997 Jan
PMID:Sequence-specific interactions of minor groove binders with the 154 base pair HindIII-RsaI restriction fragment of cDNA of the human Tau 40 protein involved in pathology of Alzheimer's disease. 904 43

The potency of 2-amino-3-methylimidazo(4,5-f)quinoline (IQ) adducts to induce -2, -1 and +1 frameshift mutations has been determined on specific target DNA sequences, namely short runs of alternating GpC sequences and short runs of guanines. The genetic control of the mutational processes has been analyzed using different Escherichia coli mutants, affected either in the control or in the mutagenesis pathway of the SOS system. We have shown that IQ adducts induce very efficiently both -1 and -2 frameshift mutations in E. coli. Both types of deletion mutations are induced in bacteria without the need of SOS induction, indicating that no LexA-controlled functions, in particular the UmuDC proteins, are required for mutation fixation. We have also shown that the frequency of IQ-induced -2 frameshift mutations in alternating GC sequences increases with the length of the repetition. The efficiency of IQ adducts to induce -1 and -2 frameshift mutations is similar to that of N-2-acetylaminofluorene (AAF) adducts. Both chemicals are potent carcinogens which form covalent adducts at the C8 position of guanines. We suggest that in both cases the adduct-induced DNA structure allows the replication complex to perform a mutagenic bypass of the lesion by a slippage mechanism. However, in contrast to AAF-induced frameshift mutagenesis, IQ-induced frameshift mutagenesis is SOS-independent.
Mol Gen Genet 1997 Feb 20
PMID:Adducts formed by the food mutagen 2-amino-3-methylimidazo(4,5-f) quinoline induce frameshift mutations at hot spots through an SOS-independent pathway. 906 97

The preparation from ferriprotoporphyrin IX (FP) in aqueous acid medium of the related pigments beta- and B-hematin [see G. Blauer and M. Akkawi, Biochem. Mol. Biol. Int. 35, 231 (1995)] is presented under different conditions. Both pigments are characterized by infrared spectra which differ in the range of 1600-1700 cm-1 in their strong bands with absorption peaks measured at 1648 +/- 2 cm-1 for B-hematin and at 1663 +/- 1 cm-1 for beta-hematin. The pH dependence of B-hematin formation at 37 degrees C and at different concentrations of acetic acid and FP exhibits a maximum yield near pH 4. The formation of beta-hematin at 70 degrees C shows high yield in 6 M acetic acid or in the presence of 0.028 M trichloroacetate at pH 4.6. The dependence of the yield of the pigments on the time and temperature of incubation, concentration of FP, and the presence of different electrolytes was investigated. Both B- and beta-hematin are either insoluble or very slightly soluble in different solvents at room temperature, and appear to dissociate into regular FP in strongly alkaline aqueous medium. In the presence of different quinoline-based drugs, the formation of both B- and beta-hematin at pH 4-5 is inhibited. Under certain conditions, the effect of added carboxylic acids on pigment formation is suggested to be due, at least in part, to the prevention of initial hydrogen bonding among FP carboxyl groups. For both B- and beta-hematin, branched and cyclic macromolecular structures are proposed involving linkages between an FP iron and a side-chain carboxylate group of another FP, in addition to hydrogen bonds between FP carboxyl groups. B- and beta-hematin are assumed to differ in molecular weight and the extent of bond formation. Possible mechanisms for beta-hematin production from B-hematin and certain relations between the synthetic pigments and the malaria pigment are suggested.
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PMID:Investigations of B- and beta-hematin. 911 63

Induction of chromosome aberrations and sister chromatid exchanges (SCEs) was studied in hepatocytes of F344 rats exposed in vivo to the hepatocarcinogen quinoline (Q). Hepatocytes were isolated 4-48 hr after a single dose of 200 mg/kg body weight or 24 hr after 28 repeated doses (once a day) of 25-200 mg/kg body weight/day by gastric intubation, and allowed to proliferate in Williams' medium E supplemented with epidermal growth factor. Cells were fixed after a culture period of 48 hr. A single dose of Q induced chromosome aberrations in up to 22% of metaphase cells, and SCEs with a frequency of up to 1.27 per chromosome 12 hr after the dose, while the control values were 1% and 0.63 per chromosome, respectively. Treatment with 28 repeated doses of Q induced significant chromosome aberrations and SCEs dose-dependently. Cytogenetic damage induced induced in the liver by repeated doses of Q was greater than induced by a single dose. Furthermore, Q induced replicative DNA synthesis in the liver, but failed to induce micronucleus formation in the bone marrow. The noncarcinogen 8-hydroxyquinoline was also examined and found to be essentially non-genotoxic to rat liver. These results show that Q is a genotoxic carcinogen to rat liver and the present method of in vivo cytogenetic assay should be useful for evaluating the genotoxicity of hepatocarcinogens.
Environ Mol Mutagen 1997
PMID:Quinoline-induced chromosome aberrations and sister chromatid exchanges in rat liver. 943 87

Green tea and black tea inhibit the formation of carcinogen-DNA adducts and colonic aberrant crypts in rats given 2-amino-3-methylimidazo[4, 5-f]quinoline (IQ), a mutagen from cooked meat. The Salmonella mutagenicity assay was used in the present study to test individual constituents of tea as inhibitors of 2-hydroxyamino-3-methylimidazo[4, 5-f]quinoline (N-hydroxy-IQ), a direct-acting metabolite of IQ. Testing of pure compounds at doses relevant to their levels in tea identified epigallocatechin (EGC) and epigalocatechin-3-gallate (EGCG) as the primary antimutagens. Studies of the inhibitory mechanisms established that the rate of degradation of N-hydroxy-IQ under aqueous conditions was not increased significantly in the presence of tea, in contrast to the results obtained with the complexing agent chlorophyllin (CHL), which rapidly degraded the mutagen. Interaction between N-hydroxy-IQ and several tea constituents was detected in spectrophotometric studies, but the binding constants were only on the order of 1 x 10(3) M-1, suggesting that mechanisms other than complex formation might prevail under the conditions of the Salmonella assay. Comparison of the results in two different strains of Salmonella typhimurium, TA98 and TA98/1,8-DNP6, indicated that the antimutagenic activity of EGCG was dependent, at least in part, on a functional O-acetyltransferase activity in the bacteria. These studies suggest that tea constituents inhibit the enzyme(s) which generate the aryl nitrenium ion and directly scavenge the reactive electrophile, whereas CHL complexes with heterocyclic amines and facilitates the degradation of active metabolites.
Environ Mol Mutagen 1997
PMID:Effects of tea and chlorophyllin on the mutagenicity of N-hydroxy-IQ: studies of enzyme inhibition, molecular complex formation, and degradation/scavenging of the active metabolites. 943 88

On isolation of rat breast cytochrome P450, one of the proteins whose amino terminus was sequenced was CYP2A3. CYP2A3 was detected by Western blotting in cytochrome P450 fractions isolated from breast of 3-, 6-, and 9-week-old rats but was low during pregnancy and lactation. Reverse transcription-polymerase chain reaction analysis and sequencing of the PCR product confirmed the presence and identity of CYP2A3 in the rat breast. Breast microsomal coumarin-7-hydroxylase activity paralleled the developmental pattern observed for CYP2A3 on Western blots. In the lung, coumarin-7-hydroxylase activity was 10-fold higher than that in the breast, but the developmental pattern was similar to that in the breast. Lung microsomes from 9-week-old rats activated the heterocyclic amine 2-amino-3-methylimidazo[4,5-f]quinoline to mutagenic metabolites which could be detected with the Ames test. This activation could be inhibited by the CYP2A3 antiserum. With breast microsomes, which contain approximately 10% of the cytochrome P450 in the lung, activation of 2-amino-3-methylimidazo[4, 5-f]quinoline could not be reliably measured. Immunohistochemical localization revealed that CYP2A3 was expressed in a limited number of epithelial cells in the ducts of 6-week-old rat breast. Double staining with smooth muscle actin, a marker for myoepithelial cells, showed no staining of CYP2A3 immunoreactive cells, indicating that these cells were not myoepithelial. The data clearly show that a cytochrome P450 that can activate environmental procarcinogens is developmentally regulated and concentrated in specific cells in the breast. The peripubertal period seems to be a window in time when the breast may be more sensitive to procarcinogens that are substrates for CYP2A3.
Mol Pharmacol 1998 Mar
PMID:Identification of CYP2A3 as a major cytochrome P450 enzyme in the female peripubertal rat breast. 949 14

Bacterial methanol and glucose dehydrogenases containing a novel type of prosthetic group, subsequently identified as pyrrolo-quinoline quinone (PQQ), were first described about 30 years ago. Quinoproteins were originally defined as proteins containing PQQ but this definition has since been broadened to include those proteins containing other types of quinone-containing prosthetic groups, and the X-ray structures of representatives of each type of quinoprotein have recently been published. This review is mainly concerned with the structure and function of the PQQ-containing methanol dehydrogenase, whose structure has been determined at high resolution, and related proteins. Their basic structure consists of a 'propeller' fold superbarrel made up of 8-sheet 'propeller blades' which are held together by novel tryptophan-docking motifs. In methanol dehydrogenase the PQQ in the active site is coordinated to a Ca2+ ion and is maintained in position by a stacked tryptophan and a novel 8-membered ring structure made up of a disulphide bridge between adjacent cysteine residues. This review describes these features and discusses them in relation to previously proposed mechanisms for this enzyme.
Prog Biophys Mol Biol 1998
PMID:The structure and function of the PQQ-containing quinoprotein dehydrogenases. 967 Jul 73

The reduction in hemozoin content is a well known feature of chloroquine-resistant Plasmodium berghei. Using NK65-derived lines displaying increasing resistance levels, we observed an inverse relationship between the hemozoin content, and the glutathione (GSH) and glutathione S-transferase (GST) levels. Treatment of highly chloroquine-resistant-infected mice with buthionine sulfoximine (BSO), which has previously been shown to partially reverse this chloroquine resistance, led to a significant increase in hemozoin production. In vitro studies on the polymerization of ferriprotoporphirin IX (FPIX) at pH 5.0 showed that GSH partially inhibited beta-hematin synthesis, while GST had a trivial and non specific effect. Furthermore, chloroquine-sensitive parasites invading reticulocytes displayed higher GSH level and GST activity, and reduced hemozoin synthesis and susceptibility to chloroquine. We conclude that, in chloroquine resistant P.berghei, GSH can detoxify hemin within the food vacuole, thus precluding its polymerization and preventing the activity of chloroquine and other quinoline-containing drugs. It is proposed that vacuolar GSH could be ascribed to an erythrocytic origin, since the resistant lines invade reticulocytes, which contain higher levels of GSH and GST than normocytes.
Mol Biochem Parasitol 1999 Jan 25
PMID:Role of glutathione in the detoxification of ferriprotoporphyrin IX in chloroquine resistant Plasmodium berghei. 1008 Mar 90


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