An Alpha Class Mouse Glutathione S-Transferase with Exceptional Catalytic Efficiency in the Conjugation of Glutathione with 7β,8α-Dihydroxy-9α,10α-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene

Hu, Xun; Srivastava, Sanjay; Xia, Hong; Awasthi, Yogesh C.; Singh, Shivendra V.

doi:10.1074/jbc.271.51.32684

Cited by 55 publications

(60 citation statements)

References 25 publications

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“…[8][9][10][11][12] However, the GST-catalyzed conjugation of BPDE with GSH is believed to be the most important enzymatic mechanism for its inactivation since ectopic expression of GSTs offer significant protection against BPDE-induced DNA damage. [13][14][15] Despite significant progress towards our understanding of the mechanisms for inactivation of BPDE, [8][9][10][11][12][13][14][15] cellular responses to BPDE exposure are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

p53 Regulates Cellular Responses to Environmental Carcinogen Benzo[a]pyrene-7,8-diol-9,10-epoxide in Human Lung Cancer Cells

Xiao

Singh²

2007

Cell Cycle

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The p53 tumor suppressor is a mutational target of environmental carcinogen anti-benzo . We now demonstrate that p53 plays an important role in regulation of cellular responses to BPDE. Exposure of p53-null H1299 human lung cancer cells to BPDE resulted in S and G 2 phase cell cycle arrest, but not mitotic block, which correlated with induction of cyclin B1 protein expression, down-modulation of cell division cycle 25C (Cdc25C) and Cdc25B protein levels, and hyperphosphorylation of Cdc25C (S216), cyclin-dependent kinase 1 (Cdk1; Y15), checkpoint kinase 1 (Chk1; S317 and S345) and Chk2 (T68). The BPDE-induced S phase block, but not the G 2 /M phase arrest, was significantly attenuated by knockdown of Chk1 protein level. The BPDE-mediated accumulation of sub-diploid fraction (apoptotic cells) was significantly decreased in H1299 cells transiently transfected with both Chk1 and Chk2 specific siRNAs. The H460 human lung cancer cell line (wild-type p53) was relatively more sensitive to BPDE-mediated growth inhibition and enrichment of subdiploid apoptotic fraction compared with H1299 cells. The BPDE exposure failed to activate either S or G 2 phase checkpoint in H460 cells. Instead, the BPDE-treated H460 cells exhibited a nearly 8-fold increase in sub-diploid apoptotic cells that was accompanied by phosphorylation of p53 at multiple sites. Knockdown of p53 protein level in H460 cells attenuated BPDE-induced apoptosis but enforced activation of S and G 2 phase checkpoints. In conclusion, the present study points towards an important role of p53 in regulation of cellular responses to BPDE in human lung cancer cells.

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Section: Introductionmentioning

confidence: 99%

p53 Regulates Cellular Responses to Environmental Carcinogen Benzo[a]pyrene-7,8-diol-9,10-epoxide in Human Lung Cancer Cells

Xiao

Singh²

2007

Cell Cycle

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“…Covalent interaction of (ϩ)-anti-BaPDE with nucleophilic sites in DNA is a critical event in BaPinduced tumorigenesis (11). Several different mechanisms exist that can convert (ϩ)-anti-BaPDE to less harmful species, and thus protect DNA (12)(13)(14)(15)(16)(17). These mechanisms include spontaneous hydrolysis to tetrols and keto diols, non-enzymatic as well as enzymatic metabolism to triols and triol epoxides, hydration by epoxide hydrolase (EH) and glutathione (GSH) S-transferase (GST)-catalyzed conjugation with GSH (12)(13)(14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Mechanism of inhibition of benzo[a]pyrene-induced forestomach cancer in mice by dietary curcumin

et al. 1998

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Curcumin (diferuloylmethane), the major yellow pigment in turmeric, has been shown to inhibit benzo[a]pyrene (BaP)-induced forestomach cancer in mice through mechanism(s) not fully understood. It is well known that while cytochrome P4501A1 (CYP1A1) and epoxide hydrolase (EH) are important in the conversion of BaP to its activated form, (⍣)-anti-7,8-dihydroxy-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(⍣)-anti-BaPDE], the detoxification of (⍣)-anti-BaPDE is accomplished by glutathione (GSH) S-transferases (GST). Therefore, it seems reasonable to postulate that curcumin may exert anti-carcinogenic activity either by inhibiting activation of BaP or (and) by enhancing the detoxification of (⍣)-anti-BaPDE. Administration p.o. of 2% curcumin in the diet to female A/J mice for 14 days, which has been shown to cause a significant inhibition in BaP-induced forestomach tumorigenesis, resulted in a modest but statistically significant reduction in hepatic ethoxyresorufin O-deethylase (EROD) activity, a reaction preferentially catalyzed by CYP1A1. While EROD activity could not be detected in the forestomach of either control or treated mice, curcumin feeding caused a statistically significant increase (~2.3-fold) in hepatic EH and GST activities. Hepatic and forestomach GSH levels, and forestomach EH and GST activities were not affected by curcumin treatment. Even though the levels of various hepatic GST isoenzymes were significantly increased upon curcumin feeding, maximum induction was noticed for the pi class isoenzyme (mGSTP1-1), which among murine hepatic GSTs is highly efficient in the detoxification of (⍣)-anti-BaPDE. In conclusion, the results of the present study suggest that curcumin may inhibit BaP-induced forestomach cancer in mice by affecting both activation as well as inactivation pathways of BaP metabolism in the liver.

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“…The tumorigenic activity of BP has been attributed to its metabolite BP-7,8-diol-9,10-epoxide (anti-BPDE), which is formed via epoxidation and hydration reactions catalyzed by cytochrome P450-dependent monooxygenases and epoxide hydrolase, respectively (2)(3)(4)(5). Anti-BPDE is highly reactive toward cellular nucleophiles, including DNA and glutathione (6,7). Covalent interaction of the epoxide functional group of anti-BPDE with exocyclic amino groups of the purine bases in DNA is considered a critical reaction in the initiation of anti-BPDE-induced cancers (7).…”

Section: Introductionmentioning

confidence: 99%

Cell Division Cycle 25B Phosphatase Is Essential for Benzo(a)Pyrene-7,8-Diol-9,10-Epoxide–Induced Neoplastic Transformation

Srivastava

Bansal²,

Oguri³

et al. 2007

Cancer Research

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Cell division cycle 25B (Cdc25B) phosphatase controls entry into mitosis and regulates recovery from G 2 -M checkpointinduced arrest. In the present study, we show that exposure of diploid mouse embryonic fibroblasts (MEF) to the ultimate carcinogen anti-benzo(a)pyrene (BP)-7,8-diol-9,10-epoxide (anti-BPDE) resulted in a concentration-and time-dependent increase in Cdc25B protein levels. Chronic exposure of wildtype (Cdc25B +/+ ) MEFs to anti-BPDE (0

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An Alpha Class Mouse Glutathione S-Transferase with Exceptional Catalytic Efficiency in the Conjugation of Glutathione with 7β,8α-Dihydroxy-9α,10α-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene

Cited by 55 publications

References 25 publications

p53 Regulates Cellular Responses to Environmental Carcinogen Benzo[a]pyrene-7,8-diol-9,10-epoxide in Human Lung Cancer Cells

p53 Regulates Cellular Responses to Environmental Carcinogen Benzo[a]pyrene-7,8-diol-9,10-epoxide in Human Lung Cancer Cells

Mechanism of inhibition of benzo[a]pyrene-induced forestomach cancer in mice by dietary curcumin

Cell Division Cycle 25B Phosphatase Is Essential for Benzo(a)Pyrene-7,8-Diol-9,10-Epoxide–Induced Neoplastic Transformation

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