Regulation of glutathione S-transferase and quinone reductase gene expression by xenobiotics

Phenobarbital is an inducer of xenobiotic-metabolizing enzymes, such as cytochrome P-450, glutathione S-transferases (GSTs) and NAD(P)H:quinone reductase, as well as being a promoter of hepatocarcinogenesis. The molecular mechanisms regulating these biological activities are, however, unknown. In this paper we show that induction by phenobarbital of GST Ya and quinone reductase gene expression is mediated by regulatory elements, EpRE and ARE respectively, which are composed of two adjacent AP-1-like binding sites. EpRE was recently found to be activated by a Fos/Jun heterodimeric complex (AP-1). Here we show that phenobarbital induces an increase in AP-1 binding activity in nuclear extracts of cultured hepatoma cells. Furthermore, we observe that the induction of chloramphenicol acetyltransferase (CAT) activity from an EpRE Ya-cat gene construct and of AP-1 binding activity by phenobarbital is inhibited by the thiol compounds N-acetyl-L-cysteine and glutathione. These results suggest that the phenobarbital induction of AP-1 activity, leading to the AP-1-mediated transcriptional activation of the GST Ya and quinone reductase genes, may involve production of reactive oxygen species and an increase in intracellular oxidant levels, which is prevented by thiol compounds. In view of the involvement of AP-1 in the control of cell proliferation and transformation, the induction by phenobarbital of AP-1 binding activity observed here provides a possible molecular mechanism for the tumour-promoting activity of this drug.

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Chemoprotective Effects of Propolis on Aflatoxin B1-Induced Hepatotoxicity in Rats: Oxidative Damage and Hepatotoxicity by Modulating TP53, Oxidative Stress

Current Proteomics ◽

10.2174/1570164617666190925121720 ◽

2020 ◽

Vol 17 (3) ◽

pp. 191-199

Author(s):

Seval Yilmaz ◽

Fatih Mehmet Kandemir ◽

Emre Kaya ◽

Mustafa Ozkaraca

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Oxidative Damage ◽

Aflatoxin B1 ◽

Tp53 Gene ◽

Control Group ◽

Glutathione S Transferase ◽

Gene Expressions ◽

Cat Gene ◽

Gst Activity

Objective: This study aimed to detect hepatic oxidative damage caused by aflatoxin B1 (AFB1), as well as to examine how propolis protects against hepatotoxic effects of AFB1. Method: Rats were split into four groups as control group, AFB1 group, propolis group, AFB1+ propolis group. Results: There was significant increase in malondialdehyde (MDA) level and tumor suppressor protein (TP53) gene expression, Glutathione (GSH) level, Catalase (CAT) activity, CAT gene expression decreased in AFB1 group in blood. MDA level and Glutathione-S-Transferase (GST) activity, GST and TP53 gene expressions increased in AFB1 group, whereas GSH level and CAT activity alongside CAT gene expression decreased in liver. AFB1+propolis group showed significant decrease in MDA level, GST activity, TP53 and GST gene expressions, GSH level and CAT activity and CAT gene expression increased in liver compared to AFB1 group. Conclusion: These results suggest that propolis may potentially be natural agent that prevents AFB1- induced oxidative stress and hepatotoxicity.

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Glutathione S-transferase omega genes in Alzheimer and Parkinson disease risk, age-at-diagnosis and brain gene expression: an association study with mechanistic implications

Molecular Neurodegeneration ◽

10.1186/1750-1326-7-13 ◽

2012 ◽

Vol 7 (1) ◽

pp. 13 ◽

Cited By ~ 42

Author(s):

Mariet Allen ◽

Fanggeng Zou ◽

High Chai ◽

Curtis S Younkin ◽

Richard Miles ◽

...

Keyword(s):

Gene Expression ◽

Parkinson Disease ◽

Association Study ◽

Disease Risk ◽

Age At Diagnosis ◽

Glutathione S Transferase ◽

Brain Gene Expression

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Regulation of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Gene Expression in FRTL-5 Cells

Journal of Biological Chemistry ◽

10.1074/jbc.270.25.15231 ◽

1995 ◽

Vol 270 (25) ◽

pp. 15231-15236 ◽

Cited By ~ 24

Author(s):

Maurizio Bifulco§ ◽

Bruno Perillo§ ◽

Motoyasu Saji ◽

Chiara Laezza§ ◽

Idolo Tedesco§ ◽

...

Keyword(s):

Gene Expression ◽

Coenzyme A ◽

Reductase Gene ◽

Coenzyme A Reductase

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Candida albicans Ferric Reductases Are Differentially Regulated in Response to Distinct Forms of Iron Limitation by the Rim101 and CBF Transcription Factors

Eukaryotic Cell ◽

10.1128/ec.00108-08 ◽

2008 ◽

Vol 7 (7) ◽

pp. 1168-1179 ◽

Cited By ~ 71

Author(s):

Yong-Un Baek ◽

Mingchun Li ◽

Dana A. Davis

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Candida Albicans ◽

Transcription Factors ◽

Iron Acquisition ◽

Mammalian Host ◽

Regulatory Sequence ◽

Ferric Reductase ◽

Reductase Gene ◽

Ferric Reductases

ABSTRACT Iron is an essential nutrient that is severely limited in the mammalian host. Candida albicans encodes a family of 15 putative ferric reductases, which are required for iron acquisition and utilization. Despite the central role of ferric reductases in iron acquisition and mobilization, relatively little is known about the regulatory networks that govern ferric reductase gene expression in C. albicans. Here we have demonstrated the differential regulation of two ferric reductases, FRE2 and FRP1, in response to distinct iron-limited environments. FRE2 and FRP1 are both induced in alkaline-pH environments directly by the Rim101 transcription factor. However, FRP1 but not FRE2 is also induced by iron chelation. We have identified a CCAAT motif as the critical regulatory sequence for chelator-mediated induction and have found that the CCAAT binding factor (CBF) is essential for FRP1 expression in iron-limited environments. We found that a hap5Δ/hap5Δ mutant, which disrupts the core DNA binding activity of CBF, is unable to grow under iron-limited conditions. C. albicans encodes three CBF-dependent transcription factors, and we identified the Hap43 protein as the CBF-dependent transcription factor required for iron-limited responses. These studies provide key insights into the regulation of ferric reductase gene expression in the fungal pathogen C. albicans.

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Doxorubicin Toxicity can be Ameliorated during Antioxidant L-Carnitine Supplementation

Oxidative Medicine and Cellular Longevity ◽

10.4161/oxim.3.6.14416 ◽

2010 ◽

Vol 3 (6) ◽

pp. 428-433 ◽

Cited By ~ 40

Author(s):

Othman A. Alshabanah ◽

Mohamed M. Hafez ◽

Mohamed M. Al-Harbi ◽

Zeinab K. Hassan ◽

Salim S. Al Rejaie ◽

...

Keyword(s):

Gene Expression ◽

Thiobarbituric Acid ◽

Albino Rats ◽

Carnitine Supplementation ◽

Glutathione S Transferase ◽

Antioxidant Genes ◽

Expression Levels ◽

High Cumulative Dose ◽

Group 2 ◽

Wistar Albino Rats

Doxorubicin is an antibiotic broadly used in treatment of different types of solid tumors. The present study investigates whether L-carnitine, antioxidant agent, can reduce the hepatic damage induced by doxorubicin. Male Wistar albino rats were divided into six groups: group 1 was intraperitoneal injected with normal saline for 10 consecutive days; group 2, 3 and 4 were injected every other day with doxorubicin (3 mg/kg, i.p.), to obtain treatments with cumulative doses of 6, 12 and 18 mg/kg. The fifth group was injected with L-carnitine (200 mg/kg, i.p.) for 10 consecutive days and the sixth group was received doxorubicin (18 mg/kg) and L-carnitine (200 mg/kg). High cumulative dose of doxorubicin (18 mg/kg) significantly increases the biochemical levels of alanine transaminase, alkaline phosphatase, total bilirubin, thiobarbituric acid reactive substances (TBARs), total nitrate/nitrite (NOx) p < 0.05 and decrease in glutathione (GSH ), superoxide dismutase (SOD), glutathione peroxidase (GSHP x), glutathione-s-transferase (GST), glutathione reductase (GR) and catalase (CAT) activity p < 0.05. The effect of doxorubicin on the activity of antioxidant genes was confirmed by real time PCR in which the expression levels of these genes in liver tissue were significantly decrease compared to control p < 0.05. Interestingly, L-carnitine supplementation completely reversed the biochemical and gene expression levels induced by doxorubicin to the control values. In conclusion, data from this study suggest that the reduction of antioxidant defense during doxorubicin administration resulted in hepatic injury could be prevented by L-carnitine supplementation by decreasing the oxidative stress and preserving both the activity and gene expression level of antioxidant enzymes.

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