Phase Ii Drug Metabolizing Enzymes

Jančová, Petra; Anzenbacher, Pavel; Anzenbacherová, Eva

doi:10.5507/bp.2010.017

Cited by 467 publications

(384 citation statements)

References 134 publications

(133 reference statements)

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“…Among all the phase 1 xenobiotic metabolizing enzymes CYP comprises 70-80%. Phase II metabolizing enzymes such as GSTP1 play an important role in biotransformation of endogenous compounds and xenobiotics to more easily excretable forms as well as in the metabolic inactivation of active compounds making them water soluble (Jancova et al, 2010;Nosheen et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Expression of CYP1A1 and GSTP1 in Human Brain Tumor Tissues in Pakistan

Wahid¹,

Mahjabeen²,

Baig³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Most of the exogenous and endogenous chemical compounds are metabolized by enzymes of xenobiotic processing pathways, including the phase I cytochrome p450 species. Carcinogens and their metabolites are generally detoxified by phase II enzymes like glutathione-S-transferases (GST). The balance of enzymes determines whether metabolic activation of pro-carcinogens or inactivation of carcinogens occurs. Under certain conditions, deregulated expression of xenobiotic enzymes may also convert endogenous substrates to metabolites that can facilitate DNA adduct formation and ultimately lead to cancer development. In this study, we aimed to test the association between deregulation of metabolizing genes and brain tumorigenesis. The expression profile of metabolizing genes CYP1A1 and GSTP1 was therefore studied in a cohort of 36 brain tumor patients and controls using Western blotting. In a second part of the study we analyzed protein expression of GSTs in the same study cohort by ELISA. CYP1A1 expression was found to be significantly high (p<0.001) in brain tumor as compared to the normal tissues, with ~4 fold (OR=4, 95%CI=0.43-37) increase in some cases. In contrast, the expression of GSTP1 was found to be significantly low in brain tumor tissues as compared to the controls (p<0.02). This down regulation was significantly higher (OR=0.05, 95%CI=0.006-0.51; p<0.007) in certain grades of lesions. Furthermore, GSTs levels were significantly down-regulated (p<0.014) in brain tumor patients compared to controls. Statistically significant decrease in GST levels was observed in the more advanced lesions (III-IV, p<0.005) as compared to the early tissue grades (I-II). Thus, altered expression of these xenobiotic metabolizing genes may be involved in brain tumor development in Pakistani population. Investigation of expression of these genes may provide information not only for the prediction of individual cancer risk but also for the prevention of cancer.

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Section: Discussionmentioning

confidence: 99%

Expression of CYP1A1 and GSTP1 in Human Brain Tumor Tissues in Pakistan

Wahid¹,

Mahjabeen²,

Baig³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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“…It has been associated with higher risk of tobacco-related cancers, such as oral and lung cancers 9 . The glutathione S transferase (GST) family includes phase II enzymes that detoxify carcinogens, reactive oxygen species and lipid peroxidation products, yielding excretable hydrophilic metabolites 10 . Individuals who have homozygous deletions for the GSTM1 gene have no GSTM1 enzyme activity.…”

Section: Introductionmentioning

confidence: 99%

Genetic polymorphism of drug metabolizing enzymes (GSTM1 and CYP1A1) as risk factors for oral premalignant lesions and oral cancer

Shukla¹,

Kale²,

Hallikerimath³

et al. 2012

BIOMED PAP

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Aims. Polymorphisms in the genes that code for metabolic enzymes involved in either the activation (Phase I) or detoxication (Phase II) of chemical carcinogens in tobacco, may alter expression or function of carcinogenic compounds and hence alter risk of oral cancer. The present study investigates whether polymorphisms at CYP1A1 and GSTM1 gene loci act as risk factors for oral precancerous lesions and cancer. Methods. For the present study, histopathologically confirmed cases of 90 oral precancerous lesions, 150 oral squamous cell carcinoma (SCC) and 150 control subjects were selected. Polymerase chain reaction and restriction fragment length polymorphism were performed using DNA from blood samples to determine the polymorphic genotypes at CYP1A1 and GSTM1 loci. Results. CYP1A1 C (m2/m2) genotype conferred a 12.0 fold-increased risk (OR=12.0; 95% CI, 2.40-60.05) to oral SCC. GSTM1 null showed no significant association but the frequency was higher in oral SCC cases. Patients with genotype C and/or GSTM1 deficiency developed carcinoma after less tobacco consumption than those of other genotypes though the difference was not statistically significant. The frequency of the combined genotypes C and GSTM1 null was found to be 14% among oral SCC patients. On comparing the susceptibility of intraoral sites it was found that in the majority of cases (64%) in the study groups they were the buccal mucosa. Conclusion. Hence it was concluded that metabolic enzymes reported in the present study: CYP1A1 significantly alter oral cancer risk. GSTM1 null and CYP1A1 C (m2m2) show a predisposition to premalignant lesions and cancer of the buccal mucosa than other sites.

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“…With rare exceptions, sulfonated metabolites are charged and hydrophilic, and therefore excreted from the human body. As a consequence, sulfonation of drugs enforce their inactivation and thus reduces their efficacy (8,9). However, sulfonation can also lead to the formation of chemically reactive or toxic metabolites (10,11).…”

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confidence: 99%

In Silico Prediction of Human Sulfotransferase 1E1 Activity Guided by Pharmacophores from Molecular Dynamics Simulations

Rakers

Schumacher

Meinl

et al. 2016

Journal of Biological Chemistry

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Acting during phase II metabolism, sulfotransferases (SULTs) serve detoxification by transforming a broad spectrum of compounds from pharmaceutical, nutritional, or environmental sources into more easily excretable metabolites. However, SULT activity has also been shown to promote formation of reactive metabolites that may have genotoxic effects. SULT subtype 1E1 (SULT1E1) was identified as a key player in estrogen homeostasis, which is involved in many physiological processes and the pathogenesis of breast and endometrial cancer. The development of an in silico prediction model for SULT1E1 ligands would therefore support the development of metabolically inert drugs and help to assess health risks related to hormonal imbalances. Here, we report on a novel approach to develop a model that enables prediction of substrates and inhibitors of SULT1E1. Molecular dynamics simulations were performed to investigate enzyme flexibility and sample protein conformations. Pharmacophores were developed that served as a cornerstone of the model, and machine learning techniques were applied for prediction refinement. The prediction model was used to screen the DrugBank (a database of experimental and approved drugs): 28% of the predicted hits were reported in literature as ligands of SULT1E1. From the remaining hits, a selection of nine molecules was subjected to biochemical assay validation and experimental results were in accordance with the in silico prediction of SULT1E1 inhibitors and substrates, thus affirming our prediction hypotheses.Metabolism plays an important role in drug discovery and appropriate metabolic profiles of new drug candidates should be taken into consideration during the process of drug development. Acting in phase I metabolism, the enzyme family of cytochrome P450 is estimated to transform about 75% of marketed drugs (1) and numerous in silico approaches for the prediction of cytochrome P450-mediated metabolism have emerged to date (2, 3). Although the majority of metabolism prediction studies focuses on phase I, the significance of phase II metabolism is generally underestimated (4) and to this day, computer-based models for the prediction of phase II metabolism remain scarce (5).Among the predominant phase II enzyme families are the soluble sulfotransferases that form a gene superfamily termed SULT. These enzymes regulate the sulfonation of smaller molecules such as endogenous hormones, neurotransmitters, and xenobiotic substances from pharmaceutical, nutritional, or environmental sources. Based on sequence similarity, functional human SULTs are divided into two main families (SULT1 and SULT2) and further into subfamilies that exhibit individual, but somewhat overlapping substrate specificities (6). Influencing the level of female sex hormones (estrogens), SULT subtype 1E1 (SULT1E1) shows a specific substrate preference for physiological estrogenic compounds (K m ϭ 5 nM for estradiol (7)) and has been extensively investigated in experimental studies.In general, sulfonation reactions in which a sulfona...

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Phase Ii Drug Metabolizing Enzymes

Cited by 467 publications

References 134 publications

Expression of CYP1A1 and GSTP1 in Human Brain Tumor Tissues in Pakistan

Expression of CYP1A1 and GSTP1 in Human Brain Tumor Tissues in Pakistan

Genetic polymorphism of drug metabolizing enzymes (GSTM1 and CYP1A1) as risk factors for oral premalignant lesions and oral cancer

In Silico Prediction of Human Sulfotransferase 1E1 Activity Guided by Pharmacophores from Molecular Dynamics Simulations

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