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1.
Toxicol Ind Health ; 31(6): 523-41, 2015 Jun.
Article in English | MEDLINE | ID: mdl-23406957

ABSTRACT

Benzo(a)pyrene (B(a)P), which is commonly used as an indicator species for polycyclic aromatic hydrocarbon (PAH) contamination, has a large number of hazardous consequences on human health. In the presence of the enzyme cytochrome-P-450 1A1 (CYP1A1), it undergoes metabolic activation to form reactive intermediates that are capable of inducing mutagenic, cytotoxic, teratogenic and carcinogenic effects in various species and tissues. Research within the last few years has shown that flavonoids exhibit chemopreventive effect against these toxins. In the present study, the protective effect of silymarin (a flavonoid) against B(a)P-induced toxicity was monitored in Wistar rats by evaluating the levels of hepatic phase I (CYP1A1), phase II enzymes (glutathione-S-transferase, epoxide hydroxylases, uridinediphosphate glucuronosyltransferases, NAD(P)H: quinone oxidoreductase 1, sulfotransferases), cellular antioxidant enzyme heme oxygenase and total glutathione. The results reveal that silymarin possesses substantial protective effect against B(a)P-induced damages by inhibiting phase I detoxification enzyme CYP1A1 and modulating phase II conjugating enzymes, which were confirmed by histopathological analysis. Overall, the inhibition of CYP1A1 and the modulation of phase II enzymes may provide, in part, the molecular basis for the effect of silymarin against B(a)P.


Subject(s)
Benzo(a)pyrene/toxicity , Chemical and Drug Induced Liver Injury/enzymology , Chemical and Drug Induced Liver Injury/prevention & control , Protective Agents/pharmacology , Silymarin/pharmacology , Animals , Cytochrome P-450 CYP1A1/metabolism , Dose-Response Relationship, Drug , Enzyme Activation , Enzyme Repression , Female , Liver/pathology , Rats , Rats, Wistar
2.
Environ Toxicol ; 29(2): 165-75, 2014 Feb.
Article in English | MEDLINE | ID: mdl-22052664

ABSTRACT

Silymarin, the purified extract from milk thistle Silybum marianum (L.) Gaertn, consists mainly of four isomeric flavonolignans: silibinin, isosilibinin, silidianin, and silichristin. The present study was carried out to evaluate the protective potential of silymarin in human erythrocytes against in vitro exposure to the carcinogen benzo(a)pyrene (B(a)P). Erythrocytes isolated from human blood were divided into four groups and treated with Vehicle [Group I], B(a)P (300 µM) [Group II], Silymarin (500 µM) + B(a)P (300 µM) [Group III], and Silymarin alone (500 µM)] [Group IV]. Silymarin treatment maintains the integrity of erythrocytes by preventing hemolysis, protein thiol oxidation and by decreasing the activity of AChE. SEM observations indicate that B(a)P induced significant alteration in the morphology of erythrocytes to echinocytes, which may be due to the interaction of B(a)P with the membrane's outer phopholipid monolayer. The light microscopic and SEM images show that silymarin treatment maintains the normal discocytic morphology of erythrocytes. The protective effect of silymarin might be attributed to its chemical structure and membranotrophic nature. The components silibinin, silydianin, and silychristin have OH in the 3rd, 5th, and 7th carbon atoms that may account for its increased antioxidant activity and removal of ROS formed during B(a)P metabolism.


Subject(s)
Benzo(a)pyrene/toxicity , Carcinogens/toxicity , Erythrocytes/drug effects , Protective Agents/pharmacology , Silymarin/pharmacology , Acetylcholinesterase/metabolism , Cell Membrane/drug effects , Cells, Cultured , Erythrocytes/metabolism , Erythrocytes/pathology , Glutathione/metabolism , Glutathione Peroxidase/metabolism , Hemolysis/drug effects , Humans , Protein Carbonylation/drug effects
3.
Asian Pac J Cancer Prev ; 12(8): 2133-8, 2011.
Article in English | MEDLINE | ID: mdl-22292665

ABSTRACT

The cytochrome P 450 1A1 gene encoding a phase I metabolic enzyme appears to be a candidate for breast cancer risk. It is involved in the phase I detoxification of polycyclic aromatic hydrocarbons (PAHs) and 2-hydroxylation of estrogens and mammary carcinogens into 2-hydroxy catechol metabolites. Several studies have investigated polymorphisms in CYP1A1 and breast cancer risk with inconsistent results. We here carried out a population based case-control study of the CYP MspI (CYP1A1*1/M1) and Ile462Val (CYP1A1*2/M2) polymorphisms in CYP1A1 to clarify their importance in determining breast cancer susceptibility in a South Indian population. A total of 50 cases and 50 controls were genotyped for both polymorphisms. We also investigated putative interactions with exposure to pollution, radiation and intake of tobacco and CYP1A1 genotype and breast cancer risk using a case only study design. The genotype distribution of CYP1A1*1 in cancer patients was 6% for homozygous (CYP1A1 M1 [C/C], 34% for heterozygous CYP1A1 M1 [T/C] and 60% for wild type (CYP1A1 M1 [T/T] (OR: 0.583, CI-95% (0.252-1.348). The genotype distribution of M2 genotypes in patients was 24% of homozygous (CYP1A1 M2 [Val/Val], 4% for heterozygous (CYP1A1 M2 [Ile/Val] and 72% for wild type allele (CYP1A1 M2 [Ile/Ile] [OR: 0.720, CI-95% (0.606-0.856)]. Our results suggest that there is no significant correlation between CYP1A1 M1/ CYP1A1 M2 polymorphism and occurrence of breast cancer in South Indian women.


Subject(s)
Breast Neoplasms/genetics , Cytochrome P-450 CYP1A1/genetics , Alleles , Breast Neoplasms/enzymology , Case-Control Studies , Codon , Dietary Fats/adverse effects , Environmental Pollution/adverse effects , Exons , Female , Genetic Predisposition to Disease , Genotype , Heterozygote , Homozygote , Humans , India , Middle Aged , Risk Factors , Smoking/adverse effects
4.
Analyst ; 135(9): 2348-54, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20596569

ABSTRACT

An electrochemical assay for sensing NO in biological systems is described in this paper. The ferrocene mediated reduction of NO, facilitated by the gold nanocomposite modified glassy carbon electrode is followed by an amperometric procedure. The analytical protocol involves the modification of a glassy carbon electrode by an overlayer of Au nanocomposites prepared through galvanic reduction. Additional overlayers can be built on the surface by repetition of the procedure. The modification leads to the decrease of the over-potential required for the analysis and results in a non-biofouling surface. Since the procedure is based on the electrochemical reduction of NO, the potential interferences from species like dopamine, ascorbic acid, etc., are overcome. The sensitivity, detection limit and response time achieved through this protocol for the modified electrode containing three Au overlayers are 0.03 nA/nM, 25.75 nM and <5 s. Analysis of NO has been carried out in real samples like liver extract, peripheral blood mononuclear cells (PBMCs) and miconazole nitrate ointment and the values obtained are comparable with that obtained by Griess analysis.


Subject(s)
Carbon/chemistry , Electrochemical Techniques/methods , Ferrous Compounds/chemistry , Gold/chemistry , Metal Nanoparticles/chemistry , Nitric Oxide/analysis , beta-Cyclodextrins/chemistry , 2-Hydroxypropyl-beta-cyclodextrin , Cell Extracts/chemistry , Dendrimers/chemistry , Electrodes , Metal Nanoparticles/ultrastructure , Metallocenes , Oxidation-Reduction
5.
Toxicol Appl Pharmacol ; 247(2): 116-28, 2010 Sep 01.
Article in English | MEDLINE | ID: mdl-20600218

ABSTRACT

PAHs are a ubiquitous class of environmental contaminants that have a large number of hazardous consequences on human health. An important prototype of PAHs, B(a)P, is notable for being the first chemical carcinogen to be discovered and the one classified by EPA as a probable human carcinogen. It undergoes metabolic activation to QD, which generate ROS by redox cycling system in the body and oxidatively damage the macromolecules. Hence, a variety of antioxidants have been tested as possible protectors against B(a)P toxicity. Silymarin is one such compound, which has high human acceptance, used clinically and consumed as dietary supplement around the world for its strong anti-oxidant efficacy. Silymarin was employed as an alternative approach for treating B(a)P induced damage and oxidative stress in PBMC, with an emphasis to provide the molecular basis for the effect of silymarin against B(a)P induced toxicity. PBMC cells exposed to either benzopyrene (1 microM) or silymarin (2.4 mg/ml) or both was monitored for toxicity by assessing LPO, PO, redox status (GSH/GSSG ratio), glutathione metabolizing enzymes GR and GPx and antioxidant enzymes CAT and SOD. This study also investigated the protective effect of silymarin against B(a)P induced biochemical alteration at the molecular level by FT-IR spectroscopy. Our findings were quite striking that silymarin possesses substantial protective effect against B(a)P induced oxidative stress and biochemical changes by restoring redox status, modulating glutathione metabolizing enzymes, hindering the formation of protein oxidation products, inhibiting LPO and further reducing ROS mediated damages by changing the level of antioxidant enzymes. The results suggest that silymarin exhibits multiple protections and it should be considered as a potential protective agent for environmental contaminant induced immunotoxicity.


Subject(s)
Antioxidants/pharmacology , Benzo(a)pyrene/toxicity , Glutathione/metabolism , Leukocytes, Mononuclear/drug effects , Protective Agents/pharmacology , Silymarin/pharmacology , Benzo(a)pyrene/antagonists & inhibitors , Catalase/metabolism , Cell Membrane/drug effects , Humans , Leukocytes, Mononuclear/metabolism , Lipid Peroxidation/drug effects , Oxidation-Reduction/drug effects , Oxidative Stress/drug effects , Superoxide Dismutase/metabolism
6.
Hum Exp Toxicol ; 29(6): 451-8, 2010 Jun.
Article in English | MEDLINE | ID: mdl-19948747

ABSTRACT

Germline polymorphisms of genes involved in different steps of tumorigenesis like p53, the tumor suppressor gene, are reported to determine the individual susceptibility to cancer. Lung cancer is one of the most common and lethal cancers and tobacco smoking remains its most important etiologic factors. The most frequently p53 mutated codons of lung cancer are 72 (exon 4) and 249 (exon 7). Since mutations in the p53 gene are present in approximately 40% of all human lung cancers and are more common in smokers than in nonsmokers, we aimed to detect the status of p53 at codon 72 for Arg/Arg or Arg/Pro or Pro/Pro allele polymorphism and p53 codon 249 mutation in smokers and nonsmokers of South India. Allele frequencies in the nonsmokers were 0.16 for the Arg/Pro allele and 0.84 for the Pro/Pro allele in our study population. Among the smokers, the frequencies of the Arg/Pro, Arg/Arg, and Pro/Pro alleles were 0.88, 0.04, and 0.08, respectively. No mutation was detected in both smokers and nonsmokers in p53 codon 249. From the worldwide scenario, it can be speculated that the smokers, with Arg/Pro genotype are more prone for lung cancer or to other types of cancer.


Subject(s)
Aging/genetics , Alcohol Drinking/genetics , Genes, p53 , Mutation , Polymorphism, Genetic , Smoking/genetics , Adolescent , Adult , Codon , Exons , Gene Frequency , Genetic Association Studies , Humans , India , Lung Neoplasms/genetics , Middle Aged , Polymorphism, Restriction Fragment Length , Restriction Mapping , Risk Factors , Young Adult
7.
Basic Clin Pharmacol Toxicol ; 100(6): 414-9, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17516996

ABSTRACT

Silymarin is a polyphenolic plant flavonoid (a mixture of flavonoid isomers such as silibinin, isosilibinin, silidianin and silichristin) derived from Silymarin marianum that has anti-inflammatory, hepatoprotective and anticarcinogenic effects. Our earlier studies have shown that silymarin plays a protective role against the oxidative damage induced by environmental contaminants like benzo(a)pyrene in erythrocyte haemolysates. During the detoxification of these environmental contaminants, the major reactive oxygen species generated is hydrogen peroxide (H(2)O(2)). Because H(2)O(2 )can easily penetrate into the cell and cause damage to biomolecules, the protective role of silymarin was further assessed against this cytotoxic agent in vitro in erythrocyte haemolysates. The protective effect was monitored by assessing the levels of the antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-s-transferase, glutathione peroxidase and malondialdehyde (LPO) in three groups: vehicle control, H(2)O(2)-exposed groups and drug co-incubation group (H(2)O(2) + silymarin). The protective effect of silymarin on the non-enzymic antioxidant glutathione and haemolysis, methaemoglobin content and protein carbonyl content were also assessed. It was observed that the activities of antioxidant enzymes and glutathione were reduced and the malondialdehyde levels were elevated after H(2)O(2 )exposure. There were also alterations in haemolysis, methaemoglobin content and protein carbonyl content, whereas after the administration of silymarin, the antioxidant enzyme activities reversed to near normal with reduced malondialdehyde content and normalized haemolysis, methaemoglobin content and protein carbonyl content. The results suggest that silymarin possesses substantial protective effect and free radical scavenging mechanism against exogenous H(2)O(2)-induced oxidative stress damages, hence, can be used as a protective drug against toxicity induced by environmental contaminants.


Subject(s)
Antioxidants/pharmacology , Environmental Pollutants/toxicity , Erythrocytes/metabolism , Hydrogen Peroxide/toxicity , Reactive Oxygen Species/metabolism , Silymarin/pharmacology , Benzo(a)pyrene/toxicity , Humans , In Vitro Techniques , Oxidoreductases/metabolism
8.
Chemosphere ; 68(8): 1511-8, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17481694

ABSTRACT

The present study was carried out to evaluate the in vitro antioxidant properties and protective effects of silymarin (milk thistle) in human erythrocyte haemolysates against benzo(a)pyrene [B(a)P], a potent carcinogenic chemical. Protective effect of silymarin was assessed in vitro by monitoring the antioxidant enzymes and malondialdehyde in three groups of haemolysates-(I) vehicle control (II) B(a)P incubated group and (III) B(a)P co incubated with silymarin. The effects of silymarin on lipid peroxidation (LPO) and antioxidant enzymes [superoxide dismutase; SOD, catalase; CAT, glutathione peroxidase; GPx, glutathione reductase; GR and glutathione-S-transferases; GST] were assessed on haemolysates. It was observed that specific activity of antioxidant enzymes were significantly decreased and the malondialdehyde levels were elevated when haemolysates were incubated with B(a)P. The protective effect of silymarin is elucidated by the significant reversal of the antioxidant enzymes and reduction in the levels of malondialdehyde. In addition, haemolysates were incubated with B(a)P for 45 min and the B(a)P metabolite, 3-hydroxy benzo(a)pyrene (3-OH-B(a)P) was detected using HPLC. An increased level of the metabolite was detected in group II. Whereas, when haemolysates were co-incubated with silymarin, the reactive metabolite 3-OH-B(a)P was not detectable which further confirms the protective role of silymarin. Generation of 3-OH-B(a)P in group II implicates the possibility of reactive oxygen species (O2- and H2O2) production in haemolysates during cytochrome P4501A1 (CYP1A1) mediated Phase-I-metabolism. Hence, we incubated the haemolysates with exogenous reactive oxygen species H2O2 and assessed the protective role of silymarin against H2O2. From the results of our study, it was suggested that silymarin possess substantial protective effect and free radical scavenging mechanism against environmental contaminants induced oxidative stress damages.


Subject(s)
Antioxidants/pharmacology , Benzo(a)pyrene/toxicity , Erythrocytes/drug effects , Hydrogen Peroxide/toxicity , Oxidative Stress/drug effects , Silymarin/pharmacology , Catalase/metabolism , Erythrocytes/enzymology , Erythrocytes/metabolism , Glutathione Reductase/metabolism , Glutathione Transferase/metabolism , Hemoglobins/analysis , Hemolysis , Humans , Lipid Peroxidation/drug effects
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