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Title: Irreversible Inhibition of Glutathione S-Transferase by Phenethyl Isothiocyanate (PEITC), a Dietary Cancer Chemopreventive Phytochemical

Authors:
; ; ; ; ; ORCiD logo;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NCINIH
OSTI Identifier:
1328024
Resource Type:
Journal Article
Resource Relation:
Journal Name: PLoS ONE; Journal Volume: 11; Journal Issue: 9
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Kumari, Vandana, Dyba, Marzena A., Holland, Ryan J., Liang, Yu-He, Singh, Shivendra V., Ji, Xinhua, and Cheng, Xiaodong. Irreversible Inhibition of Glutathione S-Transferase by Phenethyl Isothiocyanate (PEITC), a Dietary Cancer Chemopreventive Phytochemical. United States: N. p., 2016. Web. doi:10.1371/journal.pone.0163821.
Kumari, Vandana, Dyba, Marzena A., Holland, Ryan J., Liang, Yu-He, Singh, Shivendra V., Ji, Xinhua, & Cheng, Xiaodong. Irreversible Inhibition of Glutathione S-Transferase by Phenethyl Isothiocyanate (PEITC), a Dietary Cancer Chemopreventive Phytochemical. United States. doi:10.1371/journal.pone.0163821.
Kumari, Vandana, Dyba, Marzena A., Holland, Ryan J., Liang, Yu-He, Singh, Shivendra V., Ji, Xinhua, and Cheng, Xiaodong. 2016. "Irreversible Inhibition of Glutathione S-Transferase by Phenethyl Isothiocyanate (PEITC), a Dietary Cancer Chemopreventive Phytochemical". United States. doi:10.1371/journal.pone.0163821.
@article{osti_1328024,
title = {Irreversible Inhibition of Glutathione S-Transferase by Phenethyl Isothiocyanate (PEITC), a Dietary Cancer Chemopreventive Phytochemical},
author = {Kumari, Vandana and Dyba, Marzena A. and Holland, Ryan J. and Liang, Yu-He and Singh, Shivendra V. and Ji, Xinhua and Cheng, Xiaodong},
abstractNote = {},
doi = {10.1371/journal.pone.0163821},
journal = {PLoS ONE},
number = 9,
volume = 11,
place = {United States},
year = 2016,
month = 9
}
  • The commonly used anti-cancer drug chlorambucil is the primary treatment for patients with chronic lymphocytic leukaemia. Chlorambucil has been shown to be detoxified by human glutathione transferase Pi (GST P1-1), an enzyme that is often found over-expressed in cancer tissues. The allelic variants of GST P1-1 are associated with differing susceptibilities to leukaemia and differ markedly in their efficiency in catalysing glutathione (GSH) conjugation reactions. Here, we perform detailed kinetic studies of the allelic variants with the aid of three representative co-substrates. We show that the differing catalytic properties of the variants are highly substrate-dependent. We show also that allmore » variants exhibit the same temperature stability in the range 10 C to 45 C. We have determined the crystal structures of GST P1-1 in complex with chlorambucil and its GSH conjugate for two of these allelic variants that have different residues at positions 104 and 113. Chlorambucil is found to bind in a non-productive mode to the substrate-binding site (H-site) in the absence of GSH. This result suggests that under certain stress conditions where GSH levels are low, GST P1-1 can inactivate the drug by sequestering it from the surrounding medium. However, in the presence of GSH, chlorambucil binds in the H-site in a productive mode and undergoes a conjugation reaction with GSH present in the crystal. The crystal structure of the GSH-chlorambucil complex bound to the *C variant is identical with the *A variant ruling out the hypothesis that primary structure differences between the variants cause structural changes at the active site. Finally, we show that chlorambucil is a very poor inhibitor of the enzyme in contrast to ethacrynic acid, which binds to the enzyme in a similar fashion but can act as both substrate and inhibitor.« less
  • The development of multidrug resistance in MCF7 human breast cancer cells is associated with overexpression of P-glycoprotein, changes in activities of several detoxication enzymes, and loss of hormone sensitivity and estrogen receptors (ERs). The authors have cloned the cDNA for one of the drug-detoxifying enzymes overexpressed in multidrug-resistant MCF7 cells (Adr/sup R/ MCF7), the anionic isozyme of glutathione S-transferase (GST/pi/). Hybridization with this GST/pi/ cDNA, GST/pi/-1, demonstrated that increased GST/pi/ activity in Adr/sup R/ MCF7 cells is associated with overexpression but not with amplification of the gene. They mapped the GST/pi/ gene to human chromosome 11q13 by in situ hybridization.more » Since multidrug resistance and GST/pi/ overexpression are associated with the loss of ERs in Adr/sup R/ MCF7 cells, they examined several other breast cancer cell lines that were not selected for drug resistance. In each of these cell lines they found an inverse association between GST/pi/ expression and ER content. They also examined RNA from 21 primary breast cancers and found a similar association between GST/pi/ expression and ER content in vivo. The finding of similar patterns of expression of a drug-detoxifying enzyme and of ERs in vitro as well as in vivo suggests that ER-negative breast cancer cells may have greater protection against antineoplastic agents conferred by GST/pi/ than ER-positive tumors.« less
  • Purpose: To explore whether certain glutathione S-transferase (GST) polymorphisms are associated with an increased risk of breast cancer or the level of radiation-induced adverse effects after two fractionation patterns of adjuvant radiotherapy. Methods and Materials: The prevalence of germline polymorphic variants in GSTM1, GSTP1, and GSTT1 was determined in 272 breast cancer patients and compared with that in a control group of 270 women from the general population with no known history of breast cancer. The genetic variants were determined using multiplex polymerase chain reaction followed by restriction enzyme fragment analysis. In 253 of the patients surveyed for radiotherapy-induced sidemore » effects after a median observation time of 13.7 years (range, 7-22.8 years), the genotypes were related to the long-term effects observed after two fractionation patterns (treatment A, 4.3 Gy in 10 fractions for 156 patients; and treatment B, 2.5 Gy in 20 fractions for 97; both administered within a 5-week period). Results: None of the GST polymorphisms conferred an increased risk of breast cancer, either alone or in combination. Compared with treatment B, treatment A was followed by an increased level of moderate to severe radiation-induced side effects for all the endpoints studied (i.e., degree of telangiectasia, subcutaneous fibrosis and atrophy, lung fibrosis, costal fractures, and pleural thickening; p <0.001 for all endpoints). A significant association was found between the level of pleural thickening and the GSTP1 Ile105Val variant. Conclusion: The results of this study have illustrated the impact of hypofractionation on the level of adverse effects and indicated that the specific alleles of GSTP1, M1, and T1 studied here may be significant in determining the level of adverse effects after radiotherapy.« less