Curcumin and resveratrol in combination modulate drug-metabolizing enzymes as well as antioxidant indices during lung carcinogenesis in mice

2015 ◽  
Vol 34 (6) ◽  
pp. 620-627 ◽  
Author(s):  
Y Liu ◽  
Y-M Wu ◽  
Y Yu ◽  
C-S Cao ◽  
J-H Zhang ◽  
...  
Keyword(s):  
Enzyme Activities ◽  
Cytochrome B5 ◽  
Combined Treatment ◽  
Drug Metabolizing Enzymes ◽  
Lung Carcinogenesis ◽  
Glutathione S Transferase ◽  
Metabolizing Enzymes ◽  
Aryl Hydrocarbon ◽  
Noticeable Improvement ◽  
Well Differentiated

This study investigated combined chemopreventive potential of curcumin and resveratrol during benzo(a)pyrene (BP)-induced lung carcinogenesis in mice. The mice were segregated into five groups that included normal control, BP-treated, BP + curcumin-treated, BP + resveratrol-treated, and BP + curcumin + resveratrol-treated groups. A statistically significant increase in the levels of lipid peroxidation (LPO) was observed in the lungs of mice after 22 weeks of single dose of benzo(a)pyrene. Further, BP treatment also resulted in a significant increase in the enzyme activities of aryl hydrocarbon hydroxylase as well as drug-metabolizing enzymes, namely cytocrome P450 and cytochrome b5. On the other hand, reduced glutathione (GSH) levels, the activities of superoxide dismutase (SOD), glutathione reductase (GR), and glutathione- S-transferase (GST) were found to be significantly decreased following BP treatment. Supplementation with curcumin and resveratrol to BP-treated mice significantly decreased the LPO levels, GSH levels, and enzyme activities of drug-metabolizing enzymes. Further, treatment of curcumin and resveratrol to BP-treated mice significantly elevated the activities of SOD, GR, and GST. Histoarchitectural studies showed well-differentiated signs of lung carcinogenesis following BP administration to mice. However, combined treatment with curcumin and resveratrol resulted in a noticeable improvement in the lung histoarchitecture. This study, therefore, concludes that curcumin and resveratrol when supplemented in combination regulate drug-metabolizing enzymes as well as antioxidant enzymes during lung carcinogenesis in mice.

Different levels of Schistosoma mansoni infection induce changes in drug-metabolizing enzymes

1998 ◽  
Vol 72 (1) ◽  
pp. 71-78 ◽  
Author(s):  
S.A. Sheweita ◽  
S.A. Mangoura ◽  
A.G. El-Shemi
Keyword(s):  
Cytochrome P450 ◽  
Glutathione Reductase ◽  
Reduced Glutathione ◽  
The Other ◽  
Drug Metabolizing Enzymes ◽  
Mixed Function Oxidase ◽  
Glutathione S Transferase ◽  
Metabolizing Enzymes ◽  
Aryl Hydrocarbon ◽  
Different Levels

AbstractMost carcinogens and xenobiotics are metabolized primarily by the mixed function oxidase system which includes cytochrome P450, cytochrome b5, NADPH-cytochrome c reductase and aryl hydrocarbon [benzo(a)pyrene] hydroxylase. The present study investigates the influence of infection with different levels of Schistosorna mansoni cercariae on the hepatic levels of reduced glutathione, glutathione S-transferase and glutathione reductase in addition to the enzymes of mixed function oxidase. Cercariae infection levels of 60, 120, 180, 300 and 600 per mouse increased: (i) the hepatic content of cytochrome P450 by 27%, 38%, 72%, 57%, 48% respectively; (ii) the aryl hydrocarbon hydroxylase activity by 44%, 64%, 76%, 90%, 51% respectively; and (iii) the hepatic level of reduced glutathione by 67%, 83%, 103%, 60%, 38% respectively. The cytochrome b5 content did not change at the lowest level of infection but increased at the other four levels by 45%, 76%, 49% and 38% respectively. The activity of glutathione S-transferase increased at the first three levels by 42%, 40%, 27% respectively and decreased at the last two levels by 28% and 52% respectively. On the other hand, the activity of glutathione reductase did not change at any level, whereas, NADPH-cytochrome c reductase activity decreased at the last two levels by 44% and 54%. The alterations in the activities of phase I & II of drug-metabolizing enzymes as a result of infection with different levels of S. mansoni may thus change the liver's capacity to detoxify many endogenous compounds and may also potentiate the deleterious effects of aromatic hydrocarbons, e.g. benzo(a)pyrene, upon the liver and probably other organs. Such alterations may also change the therapeutic actions of drugs that are primarily metabolized by the P450 system, when administered to patients with schistosomiasis.

scholarly journals Investigation on Intestinal Proteins and Drug Metabolizing Enzymes in Simulated Microgravity Rats by a Proteomics Method

Molecules ◽  
2020 ◽  
Vol 25 (19) ◽  
pp. 4391
Author(s):  
Huayan Liu ◽  
Jingjing Guo ◽  
Yujuan Li ◽  
Yushi Zhang ◽  
Jiaping Wang ◽  
...  
Keyword(s):  
Intestinal Mucosa ◽  
Simulated Microgravity ◽  
Bioinformatic Analysis ◽  
Potential Effect ◽  
Drug Metabolizing Enzymes ◽  
Label Free ◽  
Glutathione S Transferase ◽  
Metabolizing Enzymes ◽  
Intestine Mucosa ◽  
Cyp2e1 Expression

The present study aimed to investigate the change of intestinal mucosa proteins, especially the alteration of intestinal drug metabolizing enzymes (IDMEs) following 14-day simulated microgravity. Morey–Holton tail-suspension analog was used to simulate microgravity. Intestinal mucosa proteins of rats were determined by label-free quantitative proteomic strategy. A total of 335 differentially expressed proteins (DEPs) were identified, 190 DEPs were upregulated, and 145 DEPs were downregulated. According to bioinformatic analysis, most of DEPs exhibited hydrolase, oxidoreductase, transferase, ligase, or lyase catalytic activity. DEPs were mainly enriched in metabolic pathways, including metabolism of amino acid, glucose, and carbon. Moreover, 11 of DEPs were involved in exogenous drug and xenobiotics metabolism. Owing to the importance of IDMEs for the efficacy and safety of oral drugs, the expression of cytochrome P450 1A2 (CYP1A2), CYP2D1, CYP3A2, CYP2E1, alcohol dehydrogenase 1 (ADH1), and glutathione S-transferase mu 5 (GSTM5) in rat intestine mucosa was determined by Western-blot. The activity of ADH, aldehyde dehydrogenase (ALDH) and GST was evaluated. Compared with control rats, the expression of CYP1A2, CYP2D1, CYP3A2, and ADH1 in the simulated microgravity (SMG) group of rats were dramatically decreased by 33.16%, 21.93%, 48.49%, and 22.83%, respectively. GSTM5 was significantly upregulated by 53.14% and CYP2E1 expression did not show a dramatical change in SMG group rats. Moreover, 14-day SMG reduced ADH activity, while ALDH and GST activities was not altered remarkably. It could be concluded that SMG dramatically affected the expression and activity of some IDMEs, which might alter the efficacy or safety of their substrate drugs under microgravity. The present study provided some preliminary information on IDMEs under microgravity. It revealed the potential effect of SMG on intestinal metabolism, which may be helpful to understand the intestinal health of astronauts and medication use.

scholarly journals The Modulation of Phase II Drug-Metabolizing Enzymes in Proliferating and Differentiated CaCo-2 Cells by Hop-Derived Prenylflavonoids

Nutrients ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 2138 ◽  
Author(s):  
Kateřina Lněničková ◽  
Michaela Šadibolová ◽  
Petra Matoušková ◽  
Barbora Szotáková ◽  
Lenka Skálová ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Human Organism ◽  
Intestinal Cells ◽  
Drug Metabolizing Enzymes ◽  
Uridine Diphosphate ◽  
Glutathione S Transferase ◽  
Metabolizing Enzymes ◽  
Differentiated Cells ◽  
Colorectal Cancer Cells ◽  
Glucuronosyl Transferase

Prenylflavonoids in the human organism exhibit various health-beneficial activities, although they may interfere with drugs via the modulation of the expression and/or activity of drug-metabolizing enzymes. As intestinal cells are exposed to the highest concentrations of prenylflavonoids, we decided to study the cytotoxicity and modulatory effects of the four main hop-derived prenylflavonoids on the activities and mRNA expression of the main drug-conjugating enzymes in human CaCo-2 cells. Proliferating CaCo-2 cells were used for these purposes as a model of colorectal cancer cells, and differentiated CaCo-2 cells were used as an enterocyte-like model. All the tested prenylflavonoids inhibited the CaCo-2 cells proliferation, with xanthohumol proving the most effective (IC50 8.5 µM). The prenylflavonoids modulated the activities and expressions of the studied enzymes to a greater extent in the differentiated, as opposed to the proliferating, CaCo-2 cells. In the differentiated cells, all the prenylflavonoids caused a marked increase in glutathione S-transferase and catechol-O-methyltransferase activities, while the activity of sulfotransferase was significantly inhibited. Moreover, the prenylflavonoids upregulated the mRNA expression of uridine diphosphate (UDP)-glucuronosyl transferase 1A6 and downregulated that of glutathione S-transferase 1A1/2.

scholarly journals Effects of Curcumin Analogue, 2, 6-Bis (2, 5-Dimethoxybenzylidene) Cyclohexanone (BDMC33) on the Activities of Drug-Metabolizing Enzymes in Cultured Caco-2 Cell Model

2016 ◽  
Vol 8 (01) ◽  
Author(s):  
Ndatsu Yakubu ◽  
Syahida Ahmad ◽  
Faridah Abas ◽  
Umaru Mohammed
Keyword(s):  
Aldol Condensation ◽  
Cell Model ◽  
Drug Metabolizing Enzymes ◽  
Cytochrome P450 Reductase ◽  
Systemic Delivery ◽  
Glutathione S Transferase ◽  
Curcumin Analog ◽  
Metabolizing Enzymes ◽  
Curcumin Analogues ◽  
Anti Inflammatory

Poor systemic delivery of curcumin outside the gut due to its rapid metabolism has severely limited its application to many chronic diseases. Previously, our research group synthesized curcumin analogues 2, 6-bis (2, 5-dimethoxybenzylidene) cyclohexanone (BDMC33) that has potent anti-inflammatory activities. Therefore, the aim of this study is to evaluate the effects of curcumin analog (BDMC33) on the activities of drug metabolizing enzymes in Caco-2 cells, which was compared with that of curcumin and 3-(2-Fluorobenzylidene)-5-(2-fluorocyclohexylmethylene)-piperidin-4-one (EF-24). BDMC-33 was synthesized through the appropriate reaction of the aromatic aldehyde with cyclohexanone, under base catalyzed aldol condensation, at the ratio of ketone: aldehyde (1:2). Activity of drug metabolizing enzymes such as NADPH-cytochrome p450 reductase (CPR), UDP-glucuronosyltransferase (UGT), glutathione-S-transferase (GST) and Sulfotransferase (SULT) in Caco-2 cells were evaluated upon exposure to 50µM of BDMC33, curcumin, and EF-24, separately, for 4 hours. The BDMC33, EF-24, and curcumin treatments did not affect the activities of UGT, GST, SULT, and CPR in respect to their controls (29.45, 27.18, 23.64 and 2.08µmol/mg), respectively, at all periods of incubation. Hence, BDMC33 was able to maintain the activities of both phases I and II drug metabolizing enzymes, and therefore it could be a potential lead, anti-inflammatory agents.

The activity of drug-metabolizing enzymes and the biotransformation of selected anthelmintics in the model tapeworm Hymenolepis diminuta

Parasitology ◽  
2012 ◽  
Vol 139 (6) ◽  
pp. 809-818 ◽  
Author(s):  
HANA BÁRTÍKOVÁ ◽  
IVAN VOKŘÁL ◽  
LENKA SKÁLOVÁ ◽  
VLADIMÍR KUBÍČEK ◽  
JANA FIRBASOVÁ ◽  
...  
Keyword(s):  
Drug Metabolism ◽  
Ex Vivo ◽  
Mass Spectrometric ◽  
Hymenolepis Diminuta ◽  
Drug Metabolizing Enzymes ◽  
Glutathione S Transferase ◽  
Methyl Derivative ◽  
Metabolizing Enzymes ◽  
Oxidative Metabolites

SUMMARYThe drug-metabolizing enzymes of some helminths can deactivate anthelmintics and therefore partially protect helminths against these drugs' toxic effect. The aim of our study was to assess the activity of the main drug-metabolizing enzymes and evaluate the metabolism of selected anthelmintics (albendazole, flubendazole, mebendazole) in the rat tapeworm Hymenolepis diminuta, a species often used as a model tapeworm. In vitro and ex vivo experiments were performed. Metabolites of the anthelmintics were detected and identified by HPLC with spectrofluorometric or mass–spectrometric detection. The enzymes of H. diminuta are able to reduce the carbonyl group of flubendazole, mebendazole and several other xenobiotics. Although the activity of a number of oxidation enzymes was determined, no oxidative metabolites of albendazole were detected. Regarding conjugation enzymes, a high activity of glutathione S-transferase was observed. A methyl derivative of reduced flubendazole was the only conjugation metabolite identified in ex vivo incubations of H. diminuta with anthelmintics. The results revealed that H. diminuta metabolized flubendazole and mebendazole, but not albendazole. The biotransformation pathways found in H. diminuta differ from those described in Moniezia expanza and suggest the interspecies differences in drug metabolism not only among classes of helminths, but even among tapeworms.

Differential lobular induction in rat liver of glutathioneS-transferase A1/A2 by phenobarbital

2000 ◽  
Vol 278 (4) ◽  
pp. G542-G550 ◽  
Author(s):  
Niazy Selim ◽  
Gene D. Branum ◽  
Xia Liu ◽  
Richard Whalen ◽  
Thomas D. Boyer
Keyword(s):  
Transcriptional Activity ◽  
Drug Metabolizing Enzymes ◽  
Glutathione S Transferase ◽  
Hepatic Lobule ◽  
Metabolizing Enzymes ◽  
Transcript Levels ◽  
Mrna Transcripts ◽  
Phenobarbital Administration ◽  
Rat Livers

Phenobarbital and other xenobiotics induce drug-metabolizing enzymes, including glutathione S-transferase A1/A2 (rGSTA1/A2). We examined the mechanism of induction of rGSTA1/A2 in rat livers after phenobarbital treatment. The induction of rGSTA1/A2 was not uniform across the hepatic lobule; steady-state transcript levels were threefold higher in perivenous hepatocytes relative to periportal hepatocytes when examined by in situ hybridization 12 h after a single dose of phenobarbital. Administration of a second dose of phenobarbital 12 or 24 h after the first dose did not equalize the induction of rGSTA1/A2 across the lobule. The transcriptional activity of the rGSTA1/A2 gene was increased 3.5- to 5.5-fold in whole liver by phenobarbital, but activities were the same in enriched periportal and perivenous subpopulations of hepatocytes from phenobarbital-treated animals. The half-life of rGSTA1/A2 mRNA in control animals was 3.6 h, whereas it was 10.2 h in phenobarbital-treated animals. We conclude that phenobarbital induces rGSTA1/A2 expression by increasing transcriptional activity across the lobule but induction of rGSTA1/A2 is greater in perivenous hepatocytes due to localized stabilization of mRNA transcripts.

Biotransformation of anthelmintics and the activity of drug-metabolizing enzymes in the tapeworm Moniezia expansa

Parasitology ◽  
2014 ◽  
Vol 142 (5) ◽  
pp. 648-659 ◽  
Author(s):  
LUKÁŠ PRCHAL ◽  
HANA BÁRTÍKOVÁ ◽  
ANETA BEČANOVÁ ◽  
ROBERT JIRÁSKO ◽  
IVAN VOKŘÁL ◽  
...  
Keyword(s):  
High Performance Liquid Chromatography ◽  
Liquid Chromatography ◽  
High Performance ◽  
Ex Vivo ◽  
Ultra Violet ◽  
Drug Metabolizing Enzymes ◽  
Glutathione S Transferase ◽  
Metabolizing Enzymes ◽  
Moniezia Expansa

SUMMARYThe sheep tapeworm Moniezia expansa is very common parasite, which affects ruminants such as sheep, goats as well as other species. The benzimidazole anthelmintics albendazole (ABZ), flubendazole (FLU) and mebendazole (MBZ) are often used to treat the infection. The drug-metabolizing enzymes of helminths may alter the potency of anthelmintic treatment. The aim of our study was to assess the activity of the main drug-metabolizing enzymes and evaluate the metabolism of selected anthelmintics (ABZ, MBZ and FLU) in M. expansa. Activities of biotransformation enzymes were determined in subcellular fractions. Metabolites of the anthelmintics were detected and identified using high performance liquid chromatography/ultra-violet/VIS/fluorescence or ultra-high performance liquid chromatography/mass spectrometry. Reduction of MBZ, FLU and oxidation of ABZ were proved as well as activities of various metabolizing enzymes. Despite the fact that the conjugation enzymes glutathione S-transferase, UDP-glucuronosyl transferase and UDP-glucosyl transferase were active in vitro, no conjugated metabolites of anthelmintics were identified either ex vivo or in vitro. The obtained results indicate that sheep tapeworm is able to deactivate the administered anthelmintics, and thus protects itself against their action.

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