Drug Biotransformation Enzyme Interactions Studies with Curcumin, Curcumin analogues and other Plant-derived Components

Vermeulen, N.P.E. [Promotor]Commandeur, J.N.M. [Copromotor

Assessment of Heavy Metal Contamination and Distribution in Surface Soils and Plants along the West Coast of Ghana

Onshore oil drilling activity is ongoing at Jubilee oil fields, Ghana. This activity could lead to heavy metal exposure with consequential adverse effects on public health in nearby coastal communities. Therefore, we assessed heavy metal levels and spatial distribution in soils and plants from the west coast of Ghana to obtain baseline values for monitoring heavy metal exposure. Surface soils were collected from six coastal communities, and analyzed for arsenic, cadmium, copper, mercury, lead, selenium and zinc using atomic absorption spectrophotometer. Mean heavy metal concentrations in soil samples were 2.06, 6.55, 0.016, 21.59, 0.18 and 39.49mg/kg for arsenic, copper, mercury, lead, selenium and zinc, respectively. Mean heavy metal concentrations in plants were 2.70, 17.47, 3.17, 91.74, 1.51 and 9.88mg/kg for arsenic, cadmium, copper, lead, selenium and zinc, respectively. Concentrations of arsenic, cadmium and lead in plants exceeded WHO/FAO permissible limits. Enrichment factor for arsenic was significant and extremely high for selenium, while geoaccumulation index showed moderate pollution for selenium. Soil contamination factors for arsenic, lead, and selenium indicated considerable contamination. In view of these findings remediation methods must be adopted to safeguard the communities. The data will be useful for future monitoring of heavy metal exposure in the communities and to assess the impact of the ongoing crude oil drilling activity on the environment

Regulation of Hemocytes in Drosophila Requires dappled Cytochrome b5

A major category of mutant hematopoietic phenotypes in Drosophila is melanotic tumors or nodules, which consist of abnormal and overproliferated blood cells, similar to granulomas. Our analyses of the melanotic mutant dappled have revealed a novel type of gene involved in blood cell regulation. The dappled gene is an essential gene that encodes cytochrome b5, a conserved hemoprotein that participates in electron transfer in multiple biochemical reactions and pathways. Viable mutations of dappled cause melanotic nodules and hemocyte misregulation during both hematopoietic waves of development. The sexes are similarly affected, but hemocyte number is different in females and males of both mutants and wild type. Additionally, initial tests show that curcumin enhances the dappled melanotic phenotype and establish screening of endogenous and xenobiotic compounds as a route for analysis of cytochrome b5 function. Overall, dappled provides a tractable genetic model for cytochrome b5, which has been difficult to study in higher organisms

Inhibition of human glutathione S-transferases by curcumin and analogues

Glutathione S-transferases (GSTs) are important phase II drug-metabolizing enzymes that play a major role in protecting cells from the toxic insults of electrophilic compounds. Curcumin, a promising chemotherapeutic agent, inhibits human GSTA1-1, GSTM1-1, and GSTP1-1 isoenzymes. In the present study, the effect of three series of curcumin analogues, 2,6-dibenzylidenecyclohexanone (A series), 2,5-dibenzylidenecyclopentanone (B series), and 1,4-pentadiene-3-one (C series) substituted analogues (n34), on these three human GST isoenzymes, and on human and rat liver cytosolic GSTs, was investigated using 1-chloro-2,4-dinitrobenzene (CDNB) as a substrate. Most of the 34 curcumin analogues showed less potent inhibitory activities towards GSTA1-1, GSTM1-1, and GSTP1-1 than the parent curcumin. Compounds B14 and C10 were the most potent inhibitors of GSTA1-1 and human liver cytosolic GSTs, with IC50 values of 0.20.6 μM. The most potent inhibitors of GSTM1-1 were C1, C3 and C10, with IC50 values of 0.20.7 μM. Similarly, GSTP1-1 was predominantly strongly inhibited by compounds of the C series C0, C1, C2 C10 and A0, with IC50 values of 0.44.6 μM. Compounds in the B series showed no significant inhibition of GSTP1-1. Molecular Operating Environment (MOE) program-based quantitative structureactivity relationship (QSAR) analyses have also suggested the relevance of Van der Waals surface area and compound lipophilicity factors for the inhibition of GSTA1-1 and GSTM1-1 and partial charge factors for GSTP1-1. These results may be useful in the design and synthesis of curcumin analogues with either more or less potency for GST inhibition. © 2009 Informa UK Ltd

Antiplasmodial Activity of Extracts of Tridax Procumbens and Phyllanthus Amarus in in Vitro Plasmodium Falciparum Culture Systems

Background: Aqueous extracts of Tridax procumbens (TP) (Compositae) and Phyllanthus amarus (PA) (Euphorbiaceae) are used in traditional medicine in Ghana to treat malaria. Previous studies have demonstrated the anti-trypanosoma, anti-bacterial and anti-HIV effects of TP and PA.Objective: To assess the antiplasmodial activity of extracts of TP and PA.Method: Aqueous extracts of TP and PA were prepared. A portion of each was freeze-dried and the remaining extracted sequentially with ethyl acetate and chloroform. Ethanolic extracts were also prepared. The antiplasmodial activity of the extracts was assessed with the 3H-hypoxanthine assay using chloroquine-resistant (Dd2) Plasmodium falciparum parasites. Chloroquine was used as the reference drug. The modified tetrazolium-based colorimetric assay was also used to evaluate the red blood cell (RBC)-protective/antiplasmodial activities and cytotoxicities of the extracts.Results: Results showed that TP and PA have antiplasmodial activities. The aqueous and ethanolic extracts of PA were the most active, yielding EC50 values of 34.9ìg/ml and 31.2ìg/ml, respectively in the tetrazolium-based assay. The TP and PA produced and IC50 values of 24.8ìg/ml and 11.7ìg/ml, respectively in the hypoxanthine assay. Protection of human RBCs against P. falciparum damage by the extracts highly correlated with their antiplasmodial activities. None of the extracts, within the concentration range (1.9-500ìg/ml) studied produced any overt toxicity to human RBCs.Conclusion: The results indicate that both PA and TP have activities against chloroquine-resistant P. falciparum (Dd2) parasites. The antiplasmodial principles extracted into water and ethanol but not chloroform or ethyl acetate