DSpace Angular :: Browsing by Author "Hasler, Julia A."

Browsing by Author "Hasler, Julia A."

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Cytosolic glutathione s-transferases of ostrich liver.
(2015-04-09) Naik, Yogeshkumar S.; Kanyepi, R.; Ndiweni, N.; Hasler, Julia A.; Nyathi, C.B.
Chemicals consummumed by the ostrich are likely to be metabolised by liver detoxifying enzymes such as the cytosolic glutathione Stransferases (GST). We have studied the affinity purified GST from male and female ostrich livers. 1-chloro-2, 4-dinitrobenzene (CDNB) proved to be the best of several substrates tested to measme activity. Activity with this substrate was inhibited by sulphobromoptgnalein and cibamon blue which are well established inhibitors for the m ammalian enzyme. A number of pesticides and environmentai pollutants were also found to be strong inhibitors of the enzymes. Our data indicates that ostrich liver enzymes behave similarly to the mammalian liver enzyme in terms of substrate requirements and inhibition characteristics.
Differential Effects Of Some Quinoline Antimalarial Drugs On Rat Antioxidant Enzyme Activities
(2013-03-12) Naik, Yogeshkumar S.; Magwere, Tapiwanashe; Hasler, Julia A.
Quinoline-based antimalarial drugs have played a crucial role in the fight against malaria for decades. However, with the resurgence in drug tolerance among malaria parasites worldwide. The onus is on drug designers to synthesize more effective and less toxic drugs. In this study we sought to determine the effects of quinine, and the synthetic quinolines primaquine and chloroquine, on antioxidant enzymes so as to gain a better understanding of their effects on various enzyme systems which might be of value in the development of new, safe and more effective drugs. We used the Sprague-Dawley rat as a model to study the effects of these drugs on various hepatic and renal antioxidant enzymes. Our results show that primaquine administration increased the activities of some antioxidant enzymes (superoxide dismutase, glutathione peroxidase, and catalase), whereas chloroquine increased the activity of only superoxide dismutase while decreasing that of glutathione peroxidase and catalase. These results indicate a predisposition of the organs towards oxidative damage as evidenced by increases in parameters of lipid peroxidation in the same organs. Unlike the two synthetic drugs, however, quinine did not appear to cause any significant alterations in the activities of the antioxidant enzymes and neither did it cause any oxidative damage in rat organs. From these results, we conclude that since quinoline is still an effective drug against some chloroquine-resistant strains of malaria,the renewed interest in quinoline drugs should aim to design and synthesize quinine analogues which are less toxic and have enhanced antimalarial activity.
The Effect of Schistosoma Mansoni Infection on the Hepatic Drug Metabolizing Enzymes of Mice and Hamsters
(South African Journal of Science, 1998) Naik, Yogeshkumar S.; Hasler, Julia A.
Discusses the effect of schistosome infection on hepatic drug metabolizing enzymes. Examples of drug metabolizing enzymes; Effect of liver disease of drug metabolism; Alterations in enzyme activity caused by infection; Perturbations in hepatic drug metabolizing enzyme activity with S. mansoni infection.
Effect of schistosome infection on hepatic drug metabolising enzymes
(South African Journal of Science, 1998-06) Naik, Yogeshkumar S.; Hasler, Julia A.
Schistosomiasis is a parasitic disease that affects over 200 million persons worldwide.' The disease is caused by infection with any one of several species that are known to affect humans. Infected persons are likely to be consuming a wide spectrum of xenobiotics such as drugs and environmental toxins. The drugs consumed would not only include praziquantel and other schistosomicides, but also those used for the treatment of other parasitic diseases such as antimalarials, anthelmintics and antibiotics. Experiments involving humans and experimental animals suggest that infection with schistosomes causes a reduction in the host's ability to metabolise and remove drugs from the body.
Effect of schistosome infection on hepatic drug metabolising enzymes
(1998-06) Naik, Yogeshkumar S.; Hasler, Julia A.
Schistosomiasis is a parasitic disease that affects over 200 million persons worldwide.' The disease is caused by infection with any one of several species that are known to affect humans. Infected persons are likely to be consuming a wide spectrum of xenobiotics such as drugs and environmental toxins. The drugs consumed would not only include praziquantel and other schistosomicides, but also those used for the treatment of other parasitic diseases such as antimalarials, anthelmintics and antibiotics. Experiments involving humans and experimental animals suggest that infection with schistosomes causes a reduction in the host's ability to metabolise and remove drugs from the b~dy.~.~ The metabolic fate of drugs is dependent to a large extent on the expression and activity of the microsomal drug metabolising enzyme^.^^^ These enzymes include the microsomal cytochrome P-450 dependent monooxygenase system and the uridine diphosphate glucuronosyl transferases as well as other cytosolic enzymes such as glutathione S-transferases. This article reviews the effects of experimental Schistosoma mansoni infection on hepatic drug metabolising enzyme activity.
The effect of schistosomiasis on the activation of aflatoxin B1
(1986-03) Hasler, Julia A.; Siwela, Andrew H.; Nyathi, C.B.; Chetsanga, C.J.
This study examined activation of aflatoxin Bl (AFB1) in livers of Schistosomamansoni-infected and noninfected mice by measuring covalent binding of ('H]AFBl to cellular macromolecules in vivo and in vitro. During a one week time period after AFB1 treatment of animals, maximal binding of ('H]AFB1 to DNA, RNA and protein in liver occured during the 1 - 6 hour period after treatment, with less binding throughout of AFB1 to macromolecules of infected mice. Experiments performed in vitro to determine the capacity of liver microsomes to mediate the binding of AFB1 to calf thymus DNA showed that microsomes from infected mice mediated the binding of less ('H]AFB1 to DNA than those from noninfected animals.
The effect of schistosomiasis on the covalent binding of 2-acetylaminofluorene to mouse liver macromolecules in vivo and in vitro
(Elsevier, 1990-07-15) Siwela, Andrew H.; Nyathi, C.B.; Chetsanga, C.J.; Hasler, Julia A.
The covalent binding of [14C]acetylaminofluorene (AAF) to macromolecules in vivo and in vitro was measured in Schistosoma mansoni-infected and in non-infected mice. Liver microsomes from infected mice demonstrated a 42% decreased capacity to mediate covalent binding of AAF to DNA. In addition, the extent of binding of AAF to liver macromolecules in vivo was generally less in infected than non-infected mice.
Effects of chloroquine treatment on antioxidant enzymes in rat liver and kidney.
(Elsevier Inc., 1996-05-09) Magwere, Tapiwanashe; Naik, Yogeshkumar S.; Hasler, Julia A.
The effect of chloroquine (CHQ) administration on antioxidant enzymes in rat liver and kidney was studied. Male Sprague-Dawley rats were administered 20 mglkg CHQ once a week for 4 weeks (chronic treatment) or a single dose at 10 or 20 mglkg (acute treatment). Antioxidant enzyme activities were determined in cytosolic fractions of liver and kidney, whereas reduced glutathione (GSH) and malondialdehyde (MDA) were determined in tissue samples. Results indicate minimal effects of acute CHQ treatment, whereas chronic treatment with CHQ differentially affected antioxidant enzymes in the two organs. Superoxide dismutase activity was increased nearly twofold, while activities of selenium glutathione peroxidase (GPX), catalase, and NAD (P) H: quinone oxidoreductase were decreased in livers of CHQ-treated rats compared to controls. No significant effects of CHQ on glutathione reductase, GSH, and MDA levels were seen in the liver. Fewer effects of CHQ were observed in the kidney where a decrease in GPX activity and an increase in MDA levels was seen. Lowering of antioxidant enzymes activities in the liver by CHQ could render the organ more susceptible to subsequent oxidative stress; while increased MDA production after CHQ treatment in the kidney indicate that the organ is being subjected to oxidative stress. This could have implications for prolonged chloroquine intake.
Effects of phenobarbital and 3-methylcholanthrene pretreatment on the pharmacokinetics of praziquantel in rats.
(1992-06-25) Masimirembwa, Collen M.; Naik, Yogeshkumar S.; Hasler, Julia A.
The effects of phenobarbital (PB) and 3-methylcholanthrene (MC) pretreatment on the phannac~kinetics of praziquantel (PZQ), a schistosomicide were studied in Spnrgue-Dawley rats. Blood samples at different time intervals were obtained by severing the tail vein and were analyzed for unchanged PZQ by HPLC. The PB-pretreated rats showed a &fold decrtase in AUC, a 5-fold decrease in Cmax and an 8-fold increase in Ch compared to the saline treated controls. The MC-pretreated rats and their oliveoil treated controls did not show any statistically significant diffmnces in the above parameters. These results suggest that PZQ is extensively metabolised by PB-inducible cytochrome P-450 isoforms and not by MC-inducible isoforms. These findings also suggest that the bioavailability of praziquantel could be altered to a significant extent in humans taking drugs that are phenobarbital type inducers.
Glutathione S-transferase activity in the maize weevil, sitophilus zeamais (Mostch.)
(2015-04-09) Naik, Yogeshkumar S.; Hasler, Julia A.; Giga, D.P.
Glutathione S-transferase activities in field populalions (Fo) of the maize weevil, Sitophilus zeamais, were compared with their 3rd generation (F,) progeny which were reared in the laboratory. Two substrates, 1 -chloro-2,4-dinitrobenzene (CDNB) i and glutathione (GSH) were used in the tests and the Michaelis constant (K,,,) was determined for both these substrates. Enzyme activity was detected using the CDNB as the model substrate. The K,, values using CDNB were lower for the field populations compared to the F, progeny which were reared without any exposure insecticides. The data indicate that the insects collected from the field were better able to metabolise xenobiotics than their laboratory reared progeny wl-iich were not exposed to any insecticides.
Glutathione Transferase of Schistoma Mansoni and its Interaction with Praziquantel.
(2013-03-11) Hasler, Julia A.
Glutathione S-transferases play an important role in the excretion of xenobiotics as well as in the antioxidant defence system of cells. The glutathione S-transferase of the parasitic' trematode Schistosoma mansoni has been studied. The results of preliminary experiments are presented here. The pH optimum of the enzyme was found to be 9.5 which is much higher than that of the mammalian liver enzyme. The apparent Km for the substrate 1 chloro 2,4 dinitrobenzene (CDNBL was 1.25 mN and for glutathione was 0.37 roM. The antischistosomal drug Praziquantel was found to inhibit the conjugation of CDNB in a competitive manner. The implications of these results will be discussed.
Inhibition of Glutathione S-Transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance.
(Wiley-Liss, Inc., 2001-08-06) Mukanganyama, Stanley; Widersten, Mikael; Naik, Yogeshkumar S.; Mannervik, B.; Hasler, Julia A.
A strategy to overcome multidrug resistance in cancer cells involves treatment with a combination of the antineoplastic agent and a chemomodulator that inhibits the activity of the resistance-causing protein. The aim of our study was to investigate the effects of antimalarial drugs on human recombinant glutathione S-transferase (GSTs) activity in the context of searching for effective and clinically acceptable inhibitors of these enzymes. Human recombinant GSTs heterologously expressed in Escherichia coli were used for inhibition studies. GST Al-l activity was inhibited by artemisinin with an IC,, of 6 pM, whilst GST MI-l was inhibited by quinidine and its diastereoisomer quinine with IC5,s of I2 pM and 17 pM, respectively. GST M3-3 was inhibited by tetracycline only with an IC,, of 47 pM. GST PI-l was the most susceptible enzyme to inhibition by antimalarials with IC,, values of I, 2, 1, 4, and 13 pM for pyrimethamine, arteniislnin, quinidine, quinine and tetracycline, respectively. The IC,, values obtained for artemisinin, quinine, quinidine and tetracycline are below peak plasma concentrations obtained during therapy of malaria with these drugs. It seems likely, therefore, that GSTs may be inhibited in vivo at doses normally used in clinical practice. Using the substrate ethacrynic acid, a diuretic drug also used as a modulator to overcome drug resistance in tumour cells, GST PI-l activity was inhibited by tetracycline, quinine, pyrimethamine and quinidine with IC,, values of 18, 27, 45 and 70 pM, respectively. The ubiquitous expression of GSTs in different malignancies suggests that the addition of nontoxic reversing agents such as antimalarials could enhance the efficacy of a variety of alkylating agents.
Phenotyping of the glutathione S-transferase M1 polymorphism in Zimbabweans and the effects of chloroquine on blood glutathione S-transferases M1-A
(Elsevier, 1997-05-31) Mukanganyama, Stanley; Masimirembwa, Collen M.; Naik, Yogeshkumar S.; Hasler, Julia A.
The frequency of the null allele phenotype of glutathione S-transferase (GST) M1 was investigated in 114 Zimbabweans and results for a subset of 63 subjects were compared with genotyping by PCR. In addition, the effect of the antimalarial chloroquine on blood levels of GSTMl and GSTA in 19 subjects was studied. Quantification of GSTs was by enzyme linked immunosorbent assays (ELISA). Thirty percent of the subjects were of the GSTMl null phenotype. Comparison of results of phenotyping by ELISA and genotyping by PCR showed that 16% of samples were in discordance; unknown mutations in the GSTMl gene in the Zimbabwean population may explain this observation. Chloroquine decreased levels of blood GSTM1 and GSTA by 50% or more. In populations treated with chloroquine, these decreases in GST activities might lead to compromised ability to detoxify xenobiotics, could confound GSTMl phenotyping and might invalidate use of GSTA as an indicator of liver damage. O 1997 Elsevier Science B.V. Keywords: Glutathione S-transferases; Phenotype; Black Zimbabweans; Chloroquine
Proposed Reductive Metabolism of Artemisinin by Glutathione Transferases in vitro
(The Harwood academic publishers imprint,, 2001-01-18) Naik, Yogeshkumar S.; Muganyama, Stanley; Hasler, Julia A.; Widersten, Mikael; Mannervik, B.
Artemisinin is a sesquiterpene lactone containing an endoperoxide bridge. It is a promising new antimalarial and is particularly useful against the drug resistant strains of Plasmodium fakiparum. It has unique antimalarial properties since it acts through the generation of free radicals that alkylate parasite proteins. Since the antimalarial action of the drug is antagonised by glutathionc and ascorbate and has unusual pharmacokinetic properties in humans, we have investigated if the drug is broken down by a typical reductive reaction in the presence of glutathione transferases. Cytosolic glutathione transferases (GSTs) detoxlfy electrophilic xenobiotics by catalysing the formation of glutathione (GSH) conjugates and exhibit glutathione peroxidase activity towards hydroperoxides. Arternisinin was incubated with glutathione, NADPH and glutathione reductase and G~TiSn a coupled assay syste&analogous to the standard assav scheme with cumene hv,d rover- L oxide as a substrate df GSTS. Arternisinin was shown to stimulate NADPH oxidation in cytosols from rat liver, kidney, intestines and in affinity purified preparations of GSTs from rat liver. Using human recombinant GSTs hetelorogously expressed in Escherichia coli, artemisinin was similarly shown to stimulate NADPH oxidation with the highest activity observed with GST MI-1. Using recombinant GSTs the activity of GSTs with artemisinin was at least two fold higher than the reaction with CDNB. Considering these results, it is possible that GSTs may contribute to the metabolism of artemisinin in the presence of NADPH and GSSG-reductase We propose a model, based on the known reactions of GSTs and sesquiterpenes, in which (1) artemisinin reacts with GSH resulting in oxidised glutathione; (.2) the oxidised glutathione is then converted to reduced glutathione via glutathione reductase; and (3) the latter reaction may then result in the depletion of NADPH via GSSG-reductase. The ability of artemisinin to react with GSH in the presence of GST may be responsible for the NADPH utilisation observed in vitro and suggests that cytosolic GSTs are likely to be contributing to metabolism of artemisinin and related drugs in vivo
Strain Dependant Variation In The Response Of Hepatic Drug Metabolizing Enzymes To Infection With Schistosoma Mansoni.
(2013-03-12) Naik, Yogeshkumar S.; Hasler, Julia A.
Introduction: Infection with S.mansoni has been shown to alter hepatic drug metabolising enzyme levels in mice although we have shown that hepatic drug metabolising enzymes of male hamsters are not significantly affected as a result of infection. Considerable specie and strain dependent variations do exist, however,' in the pathology of and immune response to S.mansoni infection in animals. It is not known if animals of the same specie but of different strains respond similarly to S.mansoni infection in terms of their hepatic drug metabolising enzymes. This study was therefore performed to assess the effect of S.mansoni infection on hepatic drug metabolism in vitro in male BALB/c and CBA/H mice. Results and Discussion: The results in Table 1 show that alterations in hepatic drug metabolism in vitro due to infection with S.mansoni vary between male BALB/c and CBA/H mice. Infected BALB/c and CBA/H mice both showed decreased concentrations of cytochromes P-450 and b5, and a decreased rate of ethoxyresorufin metabolism. Only infected BALB/c mice, however, showed decreases in their NADPHcytochrome c reduce activity and in the rate of ethoxycoumarin metabolism, and an increase in the rate of 4-nitroanisole metabolism. While the microsomal uridine diphosphate glucuronyl transferase activities were decreased in infected BALB/c and CBA/H mice, the cytosolic glutathione-S-transferase activities were decreased only in BALB/c mice as a result of infection. The reasons for the strain dependent difference observed here is not known. It is possible that various factors released in the circulation of animals infected with S.mansoni, such as interferons, interleukin-l, histamines etc, affect the activities of hepatic drug metabolising enzymes. Strain dependent alterations in microsomal drug metabolism have also been reported for animals pretreated with inducers of interferon synthesis. Interstrain differences among infected animals in the release of immune modulators such as those described above may be responsible for the varying effects on the hepatic drug metabolizing enzymes and their isozymes. Conclusions: It is concluded that the disposition of xenobiotics in experimental S.mansoni infected mice will vary depending on the mouse strain being used. Choice of an animal model for studies on the effect of schistosomiasis on drug metabolism should therefore be made carefully especially if extrapolation to humans is intended.
Xenobiotic metabolizing enzymes of the freshwater snails.Planorbella and lymnaea (RADIX)Natalensis.
(J. Med. and Appl. Malacol, 1994) Naik, Yogeshkumar S.; Magwere, Tapiwanashe; Matiyenga, M.; Hasler, Julia A.
Very little is known about the ability of snails to metabolise and remove xenobiotics such as molluscicides. The present study was conducted to determine whether the freshwater snails Planorbella duryi and Lymnaea (Radix) nntaIensis possess two of the major enzyme systems of detoxication, namely the P450 monooxygenase system and the glutathione Stransferases. We were able to measure microsomal cytochrome b5 and NADPH cytochrome c reductase activity, indicating a functional mixed function oxidase system. However, probing with three known substrates for the mammalian enzyme, we were unable to detect any cytochrome P450 mediated activity. Glutathione Stransferase activity was detectable in cytosolic fractions. In general, the activities detectable in snails were much lower than in mammalian liver preparations. The existence of these enzymes in snails suggests that studies should be undertaken to observe the interaction between these enzymes and xenobiotics such as candidate molluscicides. Key words: Planorbella duyi, Lyrnnaea (Radix) natalensis, cytochrome P450, glutathione

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