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Class of Glutathione S-Transferase Expression in Primary Rat Hepatocytes1
Department of Nutrition and * School of Dentistry, Chung Shan Medical University, Taichung 402, 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 (GST Yp) by sulfur amino acids. Hepatocytes isolated from male Sprague-Dawley rats were cultured with L-15-based medium containing low (LSAA; 0.1 mmol/L L-methionine and 0.1 mmol/L L-cysteine) or high (HSAA; 0.5 mmol/L L-methionine and 0.2 mmol/L L-cysteine) amounts of sulfur amino acids for up to 6 d. Cellular protein contents did not differ between LSAA- and HSAA-treated cells over the entire period. In contrast, glutathione concentrations were suppressed by the LSAA medium and on d 6 were only 20% of those of HSAA-treated cells (P < 0.05). As shown by immunoblot analysis, GST Yp protein levels were greater in LSAA-treated cells than in HSAA-treated cells (P < 0.05). The induction of GST Yp by L-methionine and L-cysteine restriction was not affected by insulin and dexamethasone, but the latter suppressed GST Yp expression (P < 0.05). LSAA increased GST Yp mRNA levels and GST activity toward ethacrynic acid (P < 0.05). GST Yp induction occurred only in cells with a limited supply of L-methionine; restriction of L-isoleucine, L-leucine, L-lysine, and L-phenylalanine had no significant effect. In contrast with the induction of GST Yp, the expression of the GST isoforms Ya and Yb was not changed by amino acid restriction. In conclusion, hepatic GST Yp gene expression is upregulated by a limited availability of sulfur amino acids.
KEY WORDS: • sulfur amino acids • glutathione S-transferase Yp • gene expression • primary hepatocytes • rats
Amino acids have multiple functions, i.e, they act as gluconeogenic substrates, as regulators of protein turnover, as neurotransmitters, and as precursors of signal transducers (1). A sufficient amino acid supply is required for normal cell growth and physiologic responses. When the amino acid supply is limited, several physiologic functions change through the regulation of the expression of numerous genes; such changes help an organism adapt to amino acid limitation. Growth retardation is one of the physiologic changes that occur with dietary protein restriction (2) and may be attributed in part to the overexpression of insulin-like growth factor binding protein 1 (IGFBP-1),3 which reduces the available concentration of insulin-like growth factor (3).
Gene transcription in response to amino acid starvation has been well studied in bacteria, such as Escherichia coli, and in eukaryotic yeast. In yeast, 2 control processes were shown, i.e., a specific control process, which is regulated by the specific amino acid end products, and a general control process, which is activated by a deficiency of any single amino acid (4,5). In mammals, however, the molecular mechanisms of gene regulation by amino acid starvation are still poorly understood (3,6,7). Candidate genes whose expression is regulated by amino acid starvation include those involved in amino acid metabolism, such as asparagine synthetase (8) and the cationic amino acid transporter cat-1 (9), and those involved in the regulation of cell growth, such as c-myc, c-jun (10), and C/EBP homologous protein (CHOP) (11). Genes involved in drug metabolism may also be modulated during protein malnutrition. In rats fed a protein-energy–deficient diet, protein levels of hepatic cytochrome P450 3A, 1A2, 2E1, and 2C1 were reduced by >50% (12,13), and such a reduction could be completely or partly normalized by simply replenishing the diet with L-cysteine or L-methionine (12). In contrast with the suppression of cytochrome P450 expression, glutathione S-transferase (GST) Ya2/3/5 and Yb1 mRNA levels in rat livers were increased by protein-energy restriction, and this increase was also normalized by L-cysteine or L-methionine supplementation (14).
GST is a phase II drug-metabolizing enzyme that catalyzes the conjugation of glutathione (GSH) with a variety of electrophilic xenobiotics and facilitates their excretion. GST is composed of 6 distinct gene families: 5 cytosolic groups (
, µ, , 
, and 
) and one microsomal form (
) (15). The families participate in a similar reaction in detoxification but have different substrate affinity. The class µ and GSTs participate in GSH conjugation with benz[a]anthracene epoxides and polycyclic aromatic hydrocarbons and also influence the production of oxidative DNA damage (16). There is growing interest in the physiologic properties of the class of GST (GST Yp), not only because of its drug detoxification activity but also because of its association with cell transformation, which may relate to carcinogenesis (17,18). GST Yp activity was used to evaluate the potency of chemoprevention agents in benzo[a]pyrene-induced cancer (19).
As stated, the induction of hepatic GST Ya2/3/5 and Yb1 mRNA levels by protein-energy restriction is reversed by simple L-cysteine or L-methionine replenishment (14). This suggests that L-cysteine or L-methionine deficiency acts to upregulate the transcription of various GST genes. It is of interest therefore to know whether the expression of other GST isozymes is also modulated in response to sulfur amino acid restriction. In the present study, we examined the activity and expression of GST Yp in primary rat hepatocytes cultured in an amino acid–restricted medium.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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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 at age 7–8 wk. Rats were treated in compliance with the NIH guidelines (20). Hepatocytes were isolated by a 2-step collagenase perfusion method as described previously (21). Cell viability was >90% as determined by trypan blue exclusion. The isolated hepatocytes were suspended in L-15 cell culture medium containing 18 mmol/L HEPES, 5 mg/L transferrin, 5 µg/L selenium as sodium selenite, 1 g/L galactose, 1 x 105/L penicillin, 100 mg/L streptomycin, and 2.5% fetal bovine serum. The cells were plated on 60-mm plastic tissue culture dishes (Falcon) precoated with rat tail collagen VII at a density of 2.5 x 106 cells per dish; the dishes were incubated in a 37°C humidified incubator in an air atmosphere. Cell attachment on the culture dish was achieved 4 h after plating, after which time the medium was changed. Thereafter, the medium was changed once daily, and the cells were cultured up to 6 d.
In Expt. 1, we investigated the effect of sulfur amino acid restriction on GST Yp expression. In this study, cells were cultured in either the L-15 control medium containing 0.5 mmol/L L-methionine and 0.2 mmol/L L-cysteine (high sulfur amino acid [HSAA] medium) or the L-15 medium containing 0.1 mmol/L L-methionine and 0.1 mmol/L L-cysteine (low sulfur amino acid [LSAA] medium). In addition, we examined the effect on GST Yp expression of insulin (5 mg/L) and dexamethasone (1 µmol/L), 2 commonly supplemented growth factors that are capable of modulating gene expression. For all treatments, cells were harvested at 24, 48, 96, and 144 h after plating.
In Expt. 2, 4 essential amino acids in addition to L-methionine and L-cysteine (L-isoleucine, L-leucine, L-lysine, and L-phenylalanine) were tested to examine whether GST Yp expression is also regulated by nonsulfur-containing amino acids. In this study, hepatocytes were exposed to either an L-15 control medium (0.5 mmol/L Met, 0.2 mmol/L Cys, 1 mmol/L Ile, 1 mmol/L Leu, 0.5 mmol/L Lys, 0.75 mmol/L Phe) or a medium restricted in a single amino acid (i.e., 0.02 mmol/L each of L-methionine, L-cysteine, L-isoleucine, L-leucine, L-lysine, or L-phenylalanine) for up to 4 d. The use of 0.02 mmol/L L-methionine was adapted from the physiologic serum concentration in rats fed a low-protein diet (3).
SDS-PAGE and immunodetection. Cells were washed twice with cold PBS and were then 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 fluid was then ultracentrifuged at 105,000 x g for an additional 1 h. Protein concentrations were measured with a Coomassie plus protein assay reagent kit (Pierce). Equal amounts of cytosolic proteins of each sample were applied to 10% SDS-PAGE gels and were transferred electrophoretically to polyvinylidene fluoride membranes as described by Towbin et al. (22). Nonspecific binding sites on the membranes were blocked at 4°C overnight with 50 g/L nonfat dry milk in buffer containing 15 mmol/L Tris and 150 mmol/L NaCl (pH 7.4). The membranes were then incubated with antibodies against GST Yp (Transduction Laboratories), Ya, Yb (Oxford Biomedical Research), or carbonic anhydrase III (CA III; kindly provided by Dr. Suzanne Hendrich, Iowa State University). After incubation with the peroxidase-conjugated secondary antibody, color was developed by adding hydrogen peroxide and tetrahydrochloride diaminobenzidine as peroxidase substrates.
Northern blot analysis.
Total RNA was extracted by using Trizol reagent. A cDNA probe was prepared by RT-PCR as described previously (23). Two pairs of oligonucleotide primers (forward: 5'-TTCAAGGCTCGCTCAAGTCCAC-3'; backward: 5'-CTTGAT-CTTGGGGCGGGCACTG-3') were designed on the basis of the published sequence of GST Yp (23,24). The PCR conditions were set as follows: denaturing at 94°C for 1 min, annealing at 55°C for 1 min, and extension at 72°C for 1 min for 35 cycles followed by a 7-min extension at 72°C. The band corresponding to the GST Yp DNA fragment was labeled with -32P-dCTP through use of an NEBlot kit (New England Biolabs) and was used as a probe. For Northern blot analysis, 20 µg of each RNA sample was separated electrophoretically on a 1%-agarose gel containing 6% formaldehyde and was then transferred to HyBond N+ membrane as previously described (23). The membrane was prehybridized for 2 h at 42°C in a solution containing 10X Denhardt’s reagent (0.2% Ficoll, 0.2% polyvinylpyrolidone, 0.2% bovine serum albumin), 5X SSPE (750 mmol/L NaCl, 50 mmol/L NaH2PO4, 5 mmol/L EDTA), 20 g/L SDS, 50% formamide, and 100 mg/L of single-stranded sheared salmon sperm DNA. The membrane was then hybridized in the same solution with an -32P-labeled GST Yp cDNA probe at 42°C overnight. After the wash, autoradiography was performed by exposing the membrane to SuperRx X-ray film (Kodak) at –80°C with an intensifying screen. The bands on the X-ray film were measured with an AlphaImager 2000 (Alpha Innotech).
Biochemical assays. GST activity was determined according to the method of Habig et al. (25) with the use of ethacrynic acid as the substrate because of its better specificity for the Yp class (26). Samples for intracellular GSH determination were prepared by adding 1 mL of 5% perchloric acid containing 2.5 mmol/L phenanthroline to each plate. The plates were scraped and the homogenates were centrifuged at 10,000 x g for 10 min. After iodoacetic acid derivation and fluoro-2,4-dinitrobenzene color development, the acid-soluble GSH and glutathione disulfide were determined by HPLC as described by Reed et al. (27).
Statistical analysis. Data were analyzed by one-way ANOVA, and Tukey’s test was used to test the significance of the effect of culture time or growth factors in each sulfur amino acid–treated group. A two-way ANOVA was used to test the interaction of sulfur amino acids and growth factors on the GST Yp protein level. The LSAA and HSAA groups were compared using Student’s t test. Differences with P-values < 0.05 were considered significant. All statistical analyses were performed with commercially available software (SAS Institute).
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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class of GST, a phase II detoxification enzyme, was upregulated when hepatocytes were cultured in a sulfur amino acid–restricted medium and that such modulation was independent of dexamethasone and insulin. Furthermore, the lack of effect of the other essential amino acids tested, e.g., L-isoleucine, L-leucine, L-lysine, and L-phenylalanine, suggests that the induction of this GST isozyme is likely sulfur amino acid specific. Amino acids are essential for maintaining normal cell function. In the face of amino acid starvation, adaptation occurs, which enhances amino acid biosynthesis by upregulating asparagine synthetase expression (29) and retards the growth rate by enhancing IGFBP expression (3). Drug metabolism in liver tissues is also modulated by feeding an energy-restricted diet (30). In contrast with the suppression of cytochrome P450 activity, GST Ya2/3/5 and Yb1 mRNA expression are upregulated by such malnutrition. Moreover, the upregulation of GST isozymes is diminished by replenishing the diet with cysteine or methionine, a finding that suggests the critical role of sulfur amino acids in the regulation of GST expression by protein-energy restriction (14). In the present study, we showed further that the expression of the Yp isozyme of GST in rat hepatocytes is enhanced by limiting the supply of sulfur amino acids in the culture medium. Although the upregulation of Yp expression occurred in cells cultured in medium restricted in L-methionine, but not in that restricted in L-cysteine, it must be emphasized that an effect of L-cysteine restriction on the regulation of GST Yp expression cannot be excluded. This lack of effect may be explained by the ability of hepatocytes to convert L-methionine to L-cysteine via the transsulfuration pathway. This newly synthesized L-cysteine acts to minimize the shortage of L-cysteine in the cell culture medium. Furthermore, L-cysteine in the medium was likely oxidized to L-cystine, thereby decreasing the availability of L-cysteine to cells. By the HPLC method (28), there was 11.4 ± 3.9% L-cysteine remaining after 24 h medium preparation (n = 3). These limitations make it difficult to determine precisely the actual effect of L-cysteine on Yp expression in this study.
The Yp isozyme of GST, little or none of which is found in normal rat liver, is continuously expressed after cell isolation, and this expression is modulated by various medium constituents, such as dexamethasone (21,31). In addition, we reported previously that FBS had a positive effect on GST Yp induction (32). In this study, we further demonstrate that the availability of sulfur amino acids modulates the expression of GST Yp in primary rat hepatocytes. Hepatocytes undergo dedifferentiation in primary culture. The induction of this detoxification enzyme seems to be the result of dedifferentiation, and this association may enhance cell survival after isolation. The expression of GST Yp is highly inducible by chemical carcinogens and is commonly used as the biochemical marker during hepatocarcinogenesis (33). The strong association of GST Yp expression with neoplastic cells has been regarded as a survival mechanism, which provides for the enhanced proliferation in a toxic environment (34).
In the present in vitro study, only GST Yp and not Ya or Yb was upregulated in response to sulfur amino acid restriction. This discrepancy in expression among the GST isozymes indicates that the gene regulation of GST Yp likely differs from that of Ya and Yb. Gene regulation involves a cascade of molecular events that activate the transcription factors, which in turn stimulate gene expression. In the GST Ya promoter/enhancer regions, 2 important DNA consensus sequences, an aryl hydrocarbon response element and an antioxidant response element (ARE) (35,36), were identified as being responsible for the induction of transcription when hepatocytes are exposed to various xenobiotics and prooxidants, including hydrogen peroxide, menadione, and tert-butyl hydroquinone (a phenolic antioxidant) (35).
Evidence suggests that the Nrf and small Maf protein families of transcription factors bind to the ARE and induce downstream genes (37,38). Activation of Nrf-1,2 binding to the ARE was shown to be important in the upregulation of hepatic GST Ya and Yb mRNA in protein-energy–malnourished rats (14). The activation of phosphatidylinositol 3-kinase caused by GSH depletion was also shown to be essential for ARE-mediated GST Ya2 induction in H4IIE hepatoma cells cultured in methionine- and cysteine-deprived medium (39). In the present study, the GST Ya level was not changed in LSAA-treated hepatocytes even when the cellular GSH content was 20% that of the HSAA-treated cells. This raises the possibility that activation of the ARE by GSH depletion is cell-type specific or that the extent of GSH depletion in hepatocytes is insufficient to activate ARE-mediated GST Ya expression.
Compared with that for GST Ya, evidence for the molecular regulation of GST Yp transcription is limited. Although there are ARE-like elements in the promoter region of GST Yp, their role in GST Yp transcription is not yet fully understood. The lack of impairment of oltipraz- or 3H-1,2-dithiole-3-thione-induced GST Yp mRNA expression in Nrf2 knockout mice (40,41) suggests that GST Yp expression is not mediated by the Nrf2-ARE pathway. However, Ikeda et al. (42) reported that Nrf2 binding to ARE-like binding sites is involved in mouse GST Yp gene induction. Rat GST Yp can be activated by Nrf2-mediated induction in H4IIE hepatoma cells, but not in normal liver cells (43). Instead, GST Yp enhancer I (GPEI), which is located at –2.5 kb, may play a key role (44). GPEI contains 2 phorbol 12-O-tetradecanote 13-acetate response element (TRE)-like elements that have activating protein (AP)-1–like binding sites (45), and both are required for the basal and inducible expression of GST Yp (46,47). For instance, the TRE is essential for the induction of GST Yp transcription by 3,4,5,3',4'-penta-chlorinated biphenyl in primary hepatocytes (46). The inhibition of GST Yp mRNA and protein expression by dexamethasone that occurred in the present study (Figs. 2and 3) was also thought to occur via the AP-1 pathway because dexamethasone acts as an antagonist of AP-1 transcription factor (31). Although the actual molecular mechanism of the sulfur amino acid induction of GST Yp gene expression is not clear, TRE is not likely the sole answer because dexamethasone seems to be ineffective in blocking the upregulation of sulfur amino acid restriction (Fig. 2). Pathways other than the glucocorticoid-suppressed AP-1 binding to TRE, such as GSH depletion-activated ARE and other unidentified factors, are possible candidates.
CHOP and asparagine synthetase (AS) are 2 of the most studied mammalian genes whose expression is regulated by amino acids. The finding that leucine restriction induces CAT activity of reporter constructs containing a CHOP or an AS promoter region supports the involvement of response elements and transcriptional factors in the amino acid–induced transcription of CHOP and AS (29,48). Even so, the pattern of CHOP and AS expression in response to amino acid restriction differs somewhat. CHOP is strongly induced by methionine deprivation and only slightly induced by deprivation of histidine, cysteine, or asparagine. AS, however, is consistently induced in response to deprivation of any one of these amino acids (49). The discrepancy in CHOP and AS expression in response to amino acid restriction indicates that the regulation of the CHOP and AS genes differs to some extent. Because GST Yp induction occurred solely with sulfur amino acid restriction and not with restriction of L-leucine, L-isoleucine, L-lysine, or L-phenylalanine, the mechanism of regulation of GST Yp by sulfur amino acids is probably different from the mechanism of regulation of CHOP and AS.
In mammals, several physiologic functions involved in the defense of or adaptation to amino acid starvation are adjusted through the regulation of the expression of numerous genes. The results of the present study clearly indicate that GST Yp gene expression is upregulated in primary rat hepatocytes by L-methionine and L-cysteine restriction. The lack of response to the other amino acids tested suggests that such an effect is probably sulfur amino acid specific. Further study is required of the molecular mechanisms involved in the regulation of GST Yp gene expression by L-methionine and L-cysteine.
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FOOTNOTES |
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3 Abbreviations used: AP, activating protein; ARE, antioxidant response element; AS, asparagine synthetase; CA III, carbonic anhydrase III; CHOP, CCAAT/enhancer-binding protein (C/EBP) homologous protein; GPEI, glutathione S-transferase Yp enhancer I; GSH, glutathione; GST, glutathione S-transferase; HSAA, high sulfur amino acid; IGFBP-1, insulin-like growth factor binding protein 1; LSAA, low sulfur amino acid; TRE, phorbol 12-O-tetradecanote 13-acetate response element.
Manuscript received 24 September 2004. Initial review completed 25 October 2004. Revision accepted 3 January 2005.
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