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Class of Glutathione S-Transferase in Rat Primary Hepatocytes1
Department of Nutrition, Chung Shan Medical University, Taichung 402, Taiwan;
* School of Dentistry, Chung Shan Medical University, Taichung 402, Taiwan; and
Graduate Institute of Food Science and Technology, National Taiwan University, Taipei 106, Taiwan
2To whom correspondence should be addressed. E-mail: cklii{at}csmu.edu.tw.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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class of glutathione S-transferase (GSTP). Hepatocytes isolated from male Sprague-Dawley rats were cultured with 50–200 µmol/L of DAS, DADS, or DATS for 24 h. DADS and DATS increased GST activity toward ethacrynic acid by 40 and 66%, respectively (P < 0.05). Moreover, both garlic allyl sulfides dose dependently induced GSTP mRNA and protein expression. DATS increased the protein level more than DADS (P < 0.05). In contrast, DAS did not affect the activity or the protein or mRNA levels of this phase II drug-metabolizing enzyme. In Clone 9 liver cells, the pTA-luciferase reporter assay showed that luciferase activity in DADS- and DATS-treated cells was 2.8- and 3.9-fold higher than that in control cells, respectively (P < 0.05). Again, luciferase activity was not affected by treatment with DAS. Deletion of –2.7 to –2.6 kb in the GSTP promoter region, which contains the GSTP enhancer (GPE) I element, abolished the upregulation of GSTP transcription by DADS and DATS. Deletion of GPE II, however, did not affect the induction of reporter activity. In conclusion, the effectiveness of 3 garlic allyl sulfides on GSTP expression was related to the number of sulfur atoms in the molecules, and GPE I was responsible for this upregulation.
KEY WORDS: • garlic organosulfur compounds • class of glutathione S-transferase • gene expression • hepatocytes • rats
Cancer chemoprevention includes the prevention, inhibition, or reversal of the process of carcinogenesis. Drug-metabolizing systems are composed of phase I and phase II enzymes. Phase I enzymes, mainly cytochrome P450, detoxify a variety of endogenous and exogenous chemicals and activate many carcinogens (1). Phase II enzyme systems, which include glutathione S-transferase (GST), 3 quinone reductase, sulfotransferases, and UDP-glucuronosyltransferase, catalyze the reduction or conjugation of phase I metabolites to various water-soluble molecules and accelerate the rate of metabolite excretion. Higher tissue levels of phase II detoxification enzymes result in lower susceptibility to carcinogenic insult (2,3).
GST catalyzes the conjugation of glutathione with a variety of electrophilic xenobiotics and facilitates their excretion. GST is composed of 6 distinct gene families, including 5 cytosolic groups (
, µ, , 
, and 
) and 1 microsomal form (
) (4). The different gene families share a similar function but differ in their substrate specificity. The class µ and GSTs are the major isozymes that participate in glutathione conjugation with benz[a]anthracene epoxides and polycyclic aromatic hydrocarbons (5). Recently, interest has been growing in the physiologic properties of the class of GST (GSTP), not only because of its action in drug detoxification but also because of its possible roles in cell transformation (6,7). Compared with other isozymes, GSTP is more effective in the detoxification of electrophilic ,ß-unsaturated carbonyl compounds that are generated by radical reactions of lipids (8). Because it is highly inducible during carcinogenesis, GSTP expression is regarded as an important determinant of cancer susceptibility and a reliable marker of tumorigenesis (9).
Two enhancing elements were identified in the 5' upstream region of the GSTP gene: GSTP enhancer (GPE) I (–2.5 kb) and GPEII (–2.2 kb) (10). The highly inducible characteristic of GSTP is generally attributed to GPEI (10), although GPEII contains the enhancer core-like sequence of simian virus 40. GPEI has two 12-O-tetradecanoylphorbol-13-acetate response-like elements (TREs), which are regulated by multiple factors, including activator protein-1 (AP-1) (11). Both TREs are thought to be required for the basal and inducible expression of GSTP (12,13).
Garlic displays diverse biological activities, including antithrombotic, antiatherosclerotic, antidiabetic, and antioxidant activities and immune modulation (14–17). Moreover, epidemiologic evidence shows that persons who consume large amounts of garlic (Allium sativum L.) in their diet have a decreased risk of stomach and colon cancers (18). The rich content of the numerous organosulfur compounds in garlic is key in garlic’s health-related functions (19). Among the garlic organosulfur compounds, diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS), which differ in their number of sulfur atoms, are the 3 major volatile allyl sulfides in garlic oil (20). The effectiveness of DAS, DADS, and DATS on the transcriptional regulation of phase I and phase II detoxification enzyme expression was shown to be positively associated with their suppression of aflatoxin B1– and benzo(a)pyrene–induced liver and forestomach neoplastic formation in mice and rats (21,22). Recently, DAS, DADS, and DATS were further shown to display differential effects in the decrease in cyclin-dependent kinase-Cdk7 and the increase in cyclin B1 protein levels in J5 human liver tumor cells and, thus, to arrest cells in the G2/M phase (23).
Structure-function relation studies indicated that the biological potency of the garlic allyl sulfides is related to their number of sulfur atoms or allyl or propyl groups (22,24). Recently, in an animal study, we reported that the induction of GSTP protein and mRNA levels in rat liver by DAS, DADS, and DATS was in the order of DATS 
DADS > DAS (24). However, the trend was not always this way and depended on the target enzyme tested. For example, the inducibility of cytochrome P450 1A1, 2B1, and 3A1 expression was negatively related to the number of sulfur atoms and was in the order of DAS > DADS > DATS (24). This discrepancy suggests that the regulatory mechanism of the 3 garlic organosulfur compounds on GSTP and cytochrome P450 differs and is worthy of further study.
Although garlic organosulfur compounds induce GSTP activity and protein expression, the molecular mechanisms of this upregulation have not yet been studied. In the present study, we first examine the efficacy of DAS, DADS, and DATS on GSTP mRNA and protein expression in rat primary hepatocytes and then construct a reporter gene to identify whether the promoter regions of the GSTP gene contain an element responsible for the upregulation of expression by allyl sulfides.
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MATERIALS AND METHODS |
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Cell isolation and culture. Male Sprague-Dawley rats were purchased from the National Laboratory Animal Center and were used for hepatocyte isolation when 7–8 wk old. Rats were treated in compliance with the NIH guidelines (25). Hepatocytes were isolated by a 2-step collagenase perfusion method as described previously (26). Cell viability was >90% as determined by trypan blue exclusion. The isolated hepatocytes were suspended in RPMI-1640 medium containing 10 mmol/L HEPES, 1 x 105 U/L penicillin, 100 mg/L streptomycin, 0.1 mmol/L dexamethasone, and 1% ITS. The cells were plated on 60-mm plastic tissue culture dishes (Nuck) precoated with rat tail collagen VII at a density of 3 x 106 cells/dish and were incubated at 37°C in a humidified atmosphere of 5% CO2 and 95% air. Cell attachment on the culture dish was achieved 48 h after plating; fresh culture media containing various concentrations of DAS, DADS, or DATS were then added for an additional 24 h. Cells treated with 0.1% dimethylsulfoxide (DMSO) alone were regarded as controls.
SDS-PAGE and immunodetection. Cells were washed twice with cold PBS and were harvested in 500 µL of 20 mmol/L potassium phosphate buffer (pH 7.0). Cell homogenates were centrifuged at 10,000 x g for 30 min at 4°C. The resultant supernatant was then ultracentrifuged at 105,000 x g for an additional 1 h. Protein content was measured by using the Coomassie Plus Protein Assay Reagent Kit (Pierce Chemical). Equal amounts of cytosolic proteins from each sample were applied to 10% SDS-polyacrylamide gels and electrophoretically transferred to polyvinylidene fluoride membranes. The nonspecific binding sites on the membranes were blocked at 4°C overnight with 50 g/L nonfat dry milk in 25 mmol/L Tris/150 mmol/L NaCl buffer, pH 7.4. The blots were then incubated sequentially with primary antibodies against GSTP (Transduction Laboratories) or actin (Sigma Chemical). After incubation with the horseradish peroxidase–conjugated secondary antibody, color was developed by adding hydrogen peroxide and tetrahydrochloride diaminobenzidine as peroxidase substrates.
Northern blot analysis.
Total RNA was extracted with Trizol reagent. The cDNA probe was prepared by RT-PCR as described previously (27). One pair of oligonucleotide primers (forward: 5'-TTCAAGGCTCGCTCAAGTCCAC-3'; reverse: 5'-CTTGATCTTGGGGCGGGCACTG-3') was designed on the basis of the published sequences of GSTP (27,28). The band corresponding to the DNA fragment of GSTP was labeled with -32P-dCTP using a NEBlot kit (New England Biolabs) and was used as the probe. For Northern blot analysis, the RNA sample was electrophoretically separated on an agarose gel and transferred to a HyBond N+ membrane (Amersham). The membrane was then prehybridized and hybridized as described (27). Autoradiography was performed by exposing the membrane to Kodak SuperRx X-ray film at –80°C with an intensifying screen. The band intensity on the X-ray film was quantitated with an AlphaImager 2000 (Alpha Innotech).
Expression and reporter constructs. The rat GSTP promoter region was generated by PCR amplification with rat genomic DNA as a template. The oligonucleotide primer (forward: 5'-GCCTCAGCTGGTAAATGGATAA-3'; reverse: 5'-AAAGGCCCCAGAGCCGCCA- GCC-3') was designed on the basis of the published sequence (10,29). The PCR reactions were performed as follows: 5 min at 94°C; 35 cycles of 40 s at 94°C, 40 s at 60°C, and 120 s at 72°C; and a final extension of 5 min at 68°C. The PCR amplicons were then electrophoresed in 1%-agarose gels containing 1X TAE buffer (40 mmol/L Tris, 20 mmol/L glacial acetic acid, and 2 mmol/L EDTA). The band corresponding to the designated length was excised, and the DNA was purified by using the QIAquick Gel Extraction Kit (Qiagen). DNA products were ligated to the pCR 2.1-TOPO vector according to the manufacturer’s instructions (Invitrogen) for amplifying and sequencing (Mission Biotech). The fragment containing –1 to –2713 bp of the GSTP gene promoter was identified. For the pTA-GSTP Luc construct, the recombinant was subcloned into a pTA-SEAP/Luc vector (Clontech). In addition to the full-length construct (pTA-2713), 2 constructs with deletions from –2713 to –2605 bp (pTA-2604) and from –2713 to –2376 bp (pTA-2375) were generated.
Transient transfection and luciferase activity assay. Clone 9 cells, which are derived from normal rat livers, were obtained from Bioresources Collection and Research Center. They were grown in RPMI-1640 medium supplemented with 10 mmol/L HEPES, 1 x 105 U/L penicillin, 100 mg/L streptomycin, and 10% fetal bovine serum at 37°C in a humidified atmosphere of 5% CO2 and 95% air. For all studies, cells with passages between 4 and 10 were used. A total of 2 x 105 cells were plated on each 35-mm plastic tissue culture dish (Nuck), and the dishes were incubated until 70% confluence was reached. Cells were transiently transfected for 4 h with 0.1 µg of the pTA-GSTP Luc vectors by lipofectamine reagent and were then changed to fresh culture media for 5 h before being exposed to DAS, DADS, DATS, or tert-butylhydroquinone (t-BHQ) for an additional 12 h. Cells were then washed twice with PBS and lysed in 100 µL of lysis buffer (Clontech). Luciferase activity was measured using Luciferase Assay Reagent (Clontech) according to the manufacturer’s instructions. The luciferase activity of each sample was corrected on the basis of ß-galactosidase activity, which was measured at 420 nm with O-nitrophenyl ß-D-galactopyranoside as a substrate. The value for cells treated with DMSO vehicle alone was set at 1.
Biochemical assays.
GST activity was measured according to the method of Habig et al. (30) using ethacrynic acid as the substrate because of its better selectivity for the class (31). Briefly, the reaction mixture in a final volume of 1 mL contained 100 mmol/L potassium phosphate buffer (pH 6.5), 0.25 mmol/L glutathione, 0.2 mmol/L ethacrynic acid, and an appropriate amount of the cytosolic proteins. The ethacrynate-glutathione conjugate formed was measured at 270 nm.
Statistical analysis. Statistical analysis was performed with commercially available software (SAS Institute). Data were analyzed using 1-way ANOVA, and the significant difference among treatment means was assessed using Tukey’s test. Differences were considered significant at P < 0.05.
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RESULTS |
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DISCUSSION |
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The results of epidemiologic studies showed that garlic consumption is inversely correlated with the incidence of certain types of cancers (18). In animal studies, garlic allyl sulfides including DAS and DADS were shown to be effective against aflatoxin B1– and azoxymethane-induced liver and colon tumorigenesis (21,33). Such an antitumorigenic effect is attributed to their modulation of phase II detoxification enzyme activity, which facilitates carcinogen clearance. Indeed, DAS and DATS were shown to increase benzo(a)pyrene excretion by upregulating GSTP expression (22). The importance of GSTP in cancer prevention is supported by the fact that 7,12-dimethylbenzanthracene–induced skin cancer was elevated significantly in GSTP-null mice (34). The effectiveness of DADS and DATS in increasing GSTP activity and expression suggests the potential application of these garlic allyl sulfides in chemoprevention (35,36).
Structure-function relation study has been used widely to examine relative biological activity among structurally related phytochemicals (22,37). In the present study, the number of sulfur atoms in DAS, DADS, and DATS was correlated with the potency of these compounds in upregulating GSTP gene expression. With a higher number of sulfur atoms, GSTP mRNA and protein levels and enzyme activity were greater (Figs. 123). This result is consistent with our previous animal study (24). It is of interest to understand how the number of sulfur atoms in the garlic allyl sulfides differentially regulates GSTP gene expression. To our knowledge, no explanation for this effect exits, and further study will be necessary to solve this puzzle. We think that DAS, DADS, and DATS may display differential activation of a specific transcriptional factor or factors, of binding to the cis-acting element on the GSTP gene promoter, and, finally, of GSTP gene transcription. In addition, the differential transportation or detoxification rate of 3 allyl sulfides in liver cells may also be one possible explanations.
Clone 9 liver cells, which are a permanently growing, nontransformed rat liver cell line (38), are derived from normal rat liver and retain an epithelial morphology (39,40). The cell line was used extensively as a model for hepatocyte function, including study of the mediation of expression of GSTP (41,42). By constructing Luc-reporters through serial deletion of the 5'-flanking region of the GSTP gene, we clearly showed that the section from –2713 to –2604 bp, which contains an enhancing element named GPE I, is required for the inducibility of GSTP expression by DADS and DATS in Clone 9 cells (Fig. 4B and C). The second enhancing element, GPE II, which is located at –2.2 kb (10), however, did not affect the induction of the GSTP gene. These findings agree with reports by others that the highly inducible characteristic of GSTP is attributed mainly to GPE I and not to GPE II (10).
In the present study, GPE I and II were identified to be located 2.7 and 2.4 kb [2.5 and 2.2 kb in the report by Sakai et al. (10)] upstream of the transcription start site and to be 
0.2 kb longer than reported by Sakai et al. The entire 2.7-kb promoter was sequenced, and the nucleotide sequences of both the 3' [–398 to –1 bp in this article and Okuda et al. (29)] and the 5' [–2713 to –2376 bp vs. –2487 to –2150 bp in Sakai et al. (10)] ends were shown to be >99% identical to the published sequences (10,29). GPE I contains 2 TRE-like elements, and both elements are required for the basal and inducible expression of GSTP (12,13). Deletion of the TRE abolishes the induction of GSTP transcription by 3,4,5,3',4'-penta-chlorinated biphenyl in primary hepatocytes (12). Several transcriptional factors, particularly AP-1, were shown to participate in the transcriptional activation of the enhancer of the GSTP gene (43). AP-1 motifs commonly compose either Jun homodimers or Jun/Fos heterodimers. It is still unclear whether Jun/Fos forms complexes with GPE I in the presence of DADS and DATS. Because of the existence of an AP-1–like binding site in the TRE, it is likely that AP-1 plays an important role in the upregulation of GSTP expression by DADS and DATS. Recently, extracellular-signal regulated kinase and c-jun N-terminal kinase, 2 upstream regulators of AP-1, were reported to be activated by DATS, and this activation is responsible for the DATS-induced apoptosis of human PC-3 prostate cancer cells (44). AP-1 mediates a wide variety of genes involved in various biological processes in cell proliferation, differentiation, transformation, apoptosis, inflammation, and immune responses (45). An understanding of the role of the AP-1–mediated signal pathway in GSTP transcriptional regulation will help clarify the possible molecular mechanism of action of the active garlic components in drug metabolism and cancer prevention (44,46).
In addition to AP-1, Nrf2 is a possible transcriptional factor that may upregulate GSTP expression because the TRE-like sequences on GPE I (5'-AGTCAGTCACTATGATTCAGCA-3') share characteristics similar to those of the antioxidant response element (ARE, 5'-GTGACTTGGCA-3'). Nrf2 forms a heterodimer with small Maf, and its binding to the ARE is responsible for the induction of the class of GST and other phase II detoxification enzymes, such as GSTP and NAD(P)H:quinone oxidoreductase (47). There is evidence that the Nrf2/ARE pathway is also important in the DADS and DATS upregulation of NAD(P)H:quinone oxidoreductase 1 and heme oxygenase (48). GSTP induction by 6-methylsulfinylhexyl isothiocyanate of wasabi was shown to be completely abrogated in Nrf2-deficient mice, which further suggests that the Nrf2/ARE pathway is likely involved in the 6-methylsulfinylhexyl isothiocyanate induction of this phase II detoxification enzyme (49). These raise the possibility that the upregulation of GSTP expression by DADS and DATS may also be dependent on Nrf2. To solve this puzzle, further study is warranted.
In conclusion, garlic allyl sulfides differentially upregulate GSTP mRNA and protein expression, and their effectiveness is related to their number of sulfur atoms. Moreover, GPEI, an enhancer element located at –2.7 kb, is required for the induction of this phase II detoxification enzyme.
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FOOTNOTES |
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3 Abbreviations used: AP-1, activator protein-1; ARE, antioxidant response element; t-BHQ, tert-butylhydroquinone; DADS, diallyl disulfide; DAS, diallyl sulfide; DATS, diallyl trisulfide; DMSO, dimethylsulfoxide; GST, glutathione S-transferase; GSTP, class of GST; GPEI, GSTP enhancer; TRE, 12-O-tetradecanoylphorbol-13-acetate response element.
Manuscript received 28 June 2005. Initial review completed 28 July 2005. Revision accepted 10 August 2005.
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  D. J. Conklin, P. Haberzettl, J.-F. Lesgards, R. A. Prough, S. Srivastava, and A. Bhatnagar Increased Sensitivity of Glutathione S-Transferase P-Null Mice to Cyclophosphamide-Induced Urinary Bladder Toxicity J. Pharmacol. Exp. Ther., November 1, 2009; 331(2): 456 - 469. [Abstract] [Full Text] [PDF]
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 D. J. Conklin, P. Haberzettl, R. A. Prough, and A. Bhatnagar Glutathione-S-transferase P protects against endothelial dysfunction induced by exposure to tobacco smoke Am J Physiol Heart Circ Physiol, May 1, 2009; 296(5): H1586 - H1597. [Abstract] [Full Text] [PDF]
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 Y.-P. Lei, H.-W. Chen, L.-Y. Sheen, and C.-K. Lii Diallyl Disulfide and Diallyl Trisulfide Suppress Oxidized LDL-Induced Vascular Cell Adhesion Molecule and E-Selectin Expression through Protein Kinase A- and B-Dependent Signaling Pathways J. Nutr., June 1, 2008; 138(6): 996 - 1003. [Abstract] [Full Text] [PDF]
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