Molecular Action Of 1,2,4-Trioxolanes In Plasmodium Falciparum, R. A. Cooper, C. L. Hartwig, E. Lauterwasser, S. Mahajan, M. Hoke, A. Renslo
Dec 2011
Molecular Action Of 1,2,4-Trioxolanes In Plasmodium Falciparum, R. A. Cooper, C. L. Hartwig, E. Lauterwasser, S. Mahajan, M. Hoke, A. Renslo
Roland A. Cooper
No abstract provided.
Sds-Page And Western Blotting Of Plasmodium Falciparum Proteins, Roland A. Cooper
Jun 2002
Sds-Page And Western Blotting Of Plasmodium Falciparum Proteins, Roland A. Cooper
Roland A. Cooper
The Plasmodium spp. parasite was identified as the causative agent of malaria in 1880, and the mosquito was identified as the vector in 1897. Despite subsequent efforts focused on the epidemiology, cell biology, immunology, molecular biology, and clinical manifestations of malaria and the Plasmodium parasite, there is still no licensed vaccine for the prevention of malaria. Physical barriers (bed nets, window screens) and chemical prevention methods (insecticides and mosquito repellents) intended to interfere with the transmission of the disease are not highly effective, and the profile of resistance of the parasite to chemoprophylactic and chemotherapeutic agents is increasing. The dawn …
Allelic Modifications Of The Cg2 And Cg1 Genes Do Not Alter The Chloroquine Response Of Drug-Resistant Plasmodium Falciparum, David A. Fidock, Takashi Nomura, Roland A. Cooper, Xin-Zhuan Su, Angela K. Talley, Thomas E. Wellems
Aug 2000
Allelic Modifications Of The Cg2 And Cg1 Genes Do Not Alter The Chloroquine Response Of Drug-Resistant Plasmodium Falciparum, David A. Fidock, Takashi Nomura, Roland A. Cooper, Xin-Zhuan Su, Angela K. Talley, Thomas E. Wellems
Roland A. Cooper
The determinant of chloroquine resistance (CQR) in a Plasmodium falciparum cross was previously mapped by linkage analysis to a 36 kb segment of chromosome 7. Candidate genes within this segment have been previously shown to include two genes, cg2 and cg1, that have complex polymorphisms linked to the CQR phenotype. Using DNA transfection and allelic exchange, we have replaced these polymorphisms in CQR parasites with cg2 and cg1 sequences from chloroquine sensitive parasites. Drug assays of the allelically-modified lines show no change in the degree of CQR, providing evidence against the hypothesis that these polymorphisms are important to the CQR …
The Relationship Between Reactivity Of Metabolites Of Pyrrolizidine Alkaloids And Extrahepatic Toxicity, R. A. Cooper, R. J. Huxtable
Dec 1998
The Relationship Between Reactivity Of Metabolites Of Pyrrolizidine Alkaloids And Extrahepatic Toxicity, R. A. Cooper, R. J. Huxtable
Roland A. Cooper
Pyrrolizidine alkaloids (PAs) are a large group of structurally similar toxins. In animals, including man, they are hepatotoxic and in some cases pneumo- and neurotoxic. PAs are metabolized by the liver P450 system to reactive dehydroalkaloid (DHA) intermediates. PA toxicity is a result of alkylation of macromolecules by DHAs. We have measured the relative reactivity of a series of semi-synthetic DHAs by recording the rate at which they alkylate a model nucleophile, 4-(p-nitrobenzyl)pyridine. Rate data fit mono- or biexponential equations. Rank order of reactivity for the macrocyclic and open ester DHAs was the same as those measured for DHA hydrolysis. …
P. Falciparum Cg2, Linked To Chloroquine Resistance, Does Not Resemble Na+/H+ Exchangers, Thomas E. Wellems, John C. Wootton, Hisashi Fujioka, Xin-Zhuan Su, Roland Cooper, Dror Baruch, David A. Frock
Aug 1998
P. Falciparum Cg2, Linked To Chloroquine Resistance, Does Not Resemble Na+/H+ Exchangers, Thomas E. Wellems, John C. Wootton, Hisashi Fujioka, Xin-Zhuan Su, Roland Cooper, Dror Baruch, David A. Frock
Roland A. Cooper
Understanding the molecular basis for chloroquine resistance in Plasmodium falciparum will provide important support for the development of new therapies and prophylactic measures against malaria. Complementary genetic and biochemical investigations should discriminate among current theories and pinpoint the functional determinants of resistance. With this in mind Sanchez et al. 1998 have proposed that the P. falciparum cg2 gene, linked by Su et al. 1997 to chloroquine resistance, may encode a sodium/hydrogen exchanger (NHE) responsible for drug transport. Here, we present evidence against this proposal. Detailed reanalysis of the CG2 sequence fails to support the claims for significant similarity to functional …
A Simple Procedure For Determining The Aqueous Half-Lives Of Pyrrolic Metabolites Of Pyrrolizidine Alkaloids, R. A. Cooper, R. J. Huxtable
Apr 1996
A Simple Procedure For Determining The Aqueous Half-Lives Of Pyrrolic Metabolites Of Pyrrolizidine Alkaloids, R. A. Cooper, R. J. Huxtable
Roland A. Cooper
We report a simple and rapid procedure for estimating the aqueous half-lives of the reactive metabolites of pyrrolizidine alkaloids that are responsible for toxicity. The metabolites (dehydroalkaloids; DHAs) were rapidly added to a 0.5 mM HEPES solution, pH 8.0. The subsequent fall in pH, due to ester hydrolysis, was followed potentiometrically. The change in pH was well described by single-component exponential decay, allowing the derivation of rate constants and half-lives of hydrolysis. Half-lives varied from 0.31 sec for dehydro-7-acetyllycopsamine to 5.36 sec for dehydrotrichodesmine. The results support the view that alkaloids whose DHA metabolites have longer half-lives produce greater extrahepatic …
Physicochemical And Metabolic Basis For The Differing Neurotoxicity Of The Pyrrolizidine Alkaloids, Trichodesmine And Monocrotaline, R. J. Huxtable, C. C. Yan, S. Wild, S. Maxwell, Roland Cooper
Jan 1996
Physicochemical And Metabolic Basis For The Differing Neurotoxicity Of The Pyrrolizidine Alkaloids, Trichodesmine And Monocrotaline, R. J. Huxtable, C. C. Yan, S. Wild, S. Maxwell, Roland Cooper
Roland A. Cooper
Monocrotaline and trichodesmine are structurally closely related pyrrolizidine alkaloids (PAs) exhibiting different extrahepatic toxicities, trichodesmine being neurotoxic (LD(50) 57 mu mol/kg) and monocrotaline pneumotoxic (LD(50) 335 mu mol/kg). We have compared certain physicochemical properties and metabolic activities of these two PAs in order to understand the quantitative and qualitative differences in toxicity. Both PAs were metabolized in the isolated, perfused rat liver to highly reactive pyrrolic dehydroalkaloids that appear to be responsible for the toxicity of PAs. More dehydrotrichodesmine (468 nmol/g liver) than dehydromonocrotaline (116 nmol/g liver) was released from liver into perfusate on perfusion for 1 hr with 0.5 …
The Sea Anemone Purine, Caissarone: Adenosine Receptor Antagonism, Roland A. Cooper, Josecarlos De Freitas, Frank Porreca, Cynthia M. Eisenhour, Ronald Lukas, Ryan J. Huxtable
Jul 1995
The Sea Anemone Purine, Caissarone: Adenosine Receptor Antagonism, Roland A. Cooper, Josecarlos De Freitas, Frank Porreca, Cynthia M. Eisenhour, Ronald Lukas, Ryan J. Huxtable
Roland A. Cooper
Caissarone, a sea anemone iminopurine, produced an increase in the twitch response of the electrically stimulated guinea-pig ileum-myenteric plexus. In the same assay, caissarone reduced the inhibitory response to the endogenous neuromodulator, adenosine, the A1 adenosine receptor agonist, R-phenylisopropyladenosine (R-PIA), and the A2 agonist, 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA) in a dose-dependent manner. Schild plot analysis of antagonism by caissarone yielded slopes of near unity, indicating that caissarone acts as a simple competitive antagonist at the adenosine receptor. The dissociation constants (KB) for caissarone ranged from 0.53 mM to 0.78 mM. In functional nicotinic receptor assays in two human cell lines, caissarone failed …
The Comparative Metabolism Of The Four Pyrrolizidine Alkaloids, Seneciphylline, Retrorsine, Monocrotaline, And Trichodesmine In The Isolated, Perfused Rat Liver., C. C. Yan, R. A. Cooper, R. J. Huxtable
Jul 1995
The Comparative Metabolism Of The Four Pyrrolizidine Alkaloids, Seneciphylline, Retrorsine, Monocrotaline, And Trichodesmine In The Isolated, Perfused Rat Liver., C. C. Yan, R. A. Cooper, R. J. Huxtable
Roland A. Cooper
Despite their similarity in structure, pyrrolizidine alkaloids (PAs) vary in their LD50s and in the organs in which toxicity is expressed. We have examined whether there are differences in the metabolism of certain PAs that are associated with these quantitative and qualitative differences in toxicity. Isolated rat livers were perfused with one of four PAs (seneciphylline, retrorsine, monocrotaline, and trichodesmine) at 0.5 mM for 1 hr, and the pyrrolic metabolites determined that were released into perfusate and bile or bound in the liver. The proportion of the PA removed by the liver varied from 93% for retrorsine to 55% for …
