Department of Environmental and Occupational Health Sciences and Center for Ecogenetics and Environmental Health, University of Washington, 4225 Roosevelt Way NE, #100, Seattle, Washington 98105
Received November 12, 2003; accepted February 15, 2004
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ABSTRACT |
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Key Words: organo(thio)phosphate esters; glutathione S-transferases; methyl parathion; human; conjugation.
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INTRODUCTION |
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The majority of OPs require cytochrome P450-mediated activation via oxidative desulfuration in order to exert their toxic effects (Fig. 1) (Butler and Murray, 1997). The resulting acute toxicity is largely, if not exclusively, due to inhibition of acetylcholinesterases by the oxon metabolites (reviewed in Namba, 1971
). Most pertinent to manifestation of toxic effects is inhibition of acetylcholinesterase in cholinergic synapses of neurons in the central nervous system and skeletal muscle.
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Based on primary sequence similarities, the mammalian GSTs can be grouped into at least eight classes termed alpha, kappa, mu, omega, pi, sigma, theta, and zeta (Board et al., 2000, 2001
; Harris et al., 1991
; Mannervik et al., 1985
; Meyer et al., 1991
; Meyer and Thomas, 1995
; Pemble et al., 1996
). In this report, we follow the unifying nomenclature system for mammalian GSTs recommended by Mannervik and colleagues (Mannervik et al., 1992
), according to which the names of the classes are abbreviated by capital letters (e.g., A for alpha, K for kappa, M for mu, O for omega, P for pi, S for sigma, T for theta, and Z for zeta) followed by Arabic numerals indicating the subunit composition, assigned in order of discovery.
The objective of this study was to investigate the ability of mammalian GSTs, in particular human GSTs, to biotransform OPs. Of particular interest are human GSTs M1-1 and T1-1; the genes for both are polymorphic due a common gene deletion. Approximately 50% and 1520% of Caucasians are homozygous null for GSTM1 and GSTT1, respectively (reviewed in Eaton and Bammler, 1999); these individuals lack the hGSTM1 and/or hGSTT1 genes and the corresponding proteins. If hGSTM1-1 and/or hGSTT1-1 played a major role(s) in the O-dealkylation of MeP in vitro, then it could be hypothesized that individuals homozygous for the null alleles would be at heightened risk for MeP poisoning. To address the mechanistic basis for this hypothesis, rat, mouse, and human hepatic cytosolic fractions have been assayed for glutathione-dependent O-demethylation activity toward MeP. Furthermore, we have determined the specific activities of several purified recombinant GSTs toward MeP, including hGSTs M1-1 and T1-1.
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MATERIALS AND METHODS |
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Animals.
Adult male Swiss-Webster mice and adult male Sprague-Dawley rats were used. The animals were sacrificed by CO2 narcosis, and the livers excised according to IACUC-approved protocols. The rats served as control animals in unrelated developmental toxicity experiments.
Human liver samples.
Ten human liver samples were obtained from the University of Washington Liver Bank (Dr. Kenneth Thummel). Characteristics of the liver donors are shown in Table 1.
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CDNB assay.
Human liver cytosols were tested for total hGST protein activity toward the model GST substrate, 1-chloro-2,4-dinitrobenzene (CDNB), as described previously (Habig and Jakoby, 1981). All reactions were linear for at least 1 min.
hGSTM1 and hGSTT1 genotyping.
The human liver samples had been previously assayed for hGSTM1 and hGSTT1 genotype by Polymerase Chain Reaction methods (Chen et al., 1996). The livers were chosen to ensure an even distribution of genotypes and genotype combinations such that two livers were GST M1+, T1+, three were GST M1+, T1 null, three were GST M1 null, T1+, and two were homozygous null for both GSTM1 and T1.
GST expression and purification.
Expression and purification of hGSTA1-1, hGSTM1a-1a, hGSTM2-2, hGSTM3-3, hGSTM4-4, mGSTA3-3, mGSTP1-1, mGSTP2-2, and rGSTA5-5 were carried out as previously described (Bammler et al., 1995). His-hGSTT1-1 construct was a generous gift from Dr. John Hayes (University of Dundee, Dundee, Scotland); expression and purification was performed as previously described (Sherratt et al., 1997
). cDNA expression constructs for hGSTs M1a, M2, M3, and M4 were generously provided by Dr. Phillip Board (John Curtis School of Medical Research, Australian National University, Canberra ACT 2601, Australia). Purified recombinant hGSTA2-2 was a kind gift from Dr. Chen-Pei D. Tu (Pennsylvania State University, State College, PA).
A hGSTP1 expression construct was generated which allowed purification of recombinant hGSTP1-1 (Abel et al, 2004). Briefly, the cDNA for hGSTP1 was generated by polymerase chain reaction amplification of an existing hGSTP1 cDNA-containing vector (a generous gift from Dr. William Atkins, University of Washington). PCR amplification primers were used that allowed for addition of NdeI and BamHI restriction sites to the 5' and 3' ends of the hGSTP1 cDNA, respectively. Subsequently, this PCR product was ligated into the pCR2.1 vector using a TA cloning kit (Invitrogen Life Technologies, Carlsbad, CA). The vector was propagated in INVF' cells. Following BamHI digestion for construct linearization, an NdeI partial digestion allowed for the collection of full-length hGSTP1 cDNA with NdeI and BamHI sticky ends for ligation into the pET17b expression vector (Novagen, Madison, WI).
Protein assays.
Protein concentrations were determined using the Bio-Rad Protein Assay (Bio-Rad Laboratories, Hercules, CA) according to the manufacturer's microtiter plate protocol. Bovine serum albumin was used as the protein standard.
MeP assay.
The assay for GST-mediated biotransformation of MeP was performed at 37°C in a shaking water bath as previously described (Anderson et al., 1992). In a 1.7-ml plastic vial, 50 µL of cytosol or recombinant GST was added to 145 µL incubation buffer (100 mM Tris, pH 7.4) with glutathione (110 mM final). The mixture was gently vortexed and prewarmed for 5 min. Following this preincubation, 5 µL of MeP was added to a final concentration of 60300 µM MeP. Following mixing, the vial was returned to the water bath for either a 10- or 30-min incubation period. Protein concentration and incubation times were modified to ensure that the reaction proceeded within the linear range for the entire incubation period. After the incubation period, the reaction was stopped with 200 µL ice-cold methanol containing 250 µM p-phenylphenol as an internal standard. Immediately following incubation the samples were stored at 20°C. Two negative controls included the replacement of protein with incubation buffer and the elimination of glutathione. Each cytosolic fraction or recombinant GST was assayed in triplicate in each of at least two trials.
Samples were prepared for HPLC/UV analysis by centrifugation at 10,000 x g for 3 min. Subsequently 200 µL of the supernatant was transferred to an HPLC vial.
HPLC protocol.
Reversed-phase HPLC with ion-pairing was used to detect the MeP metabolites and internal standard (Anderson et al., 1992). The HPLC instrumentation used for these assays was a Varian-Dynamax model SD-200 with a Varian-Dynamax Method Manager version 1.4.6 integrator. A 4.6 x 250 mm C18 RP column with Econosphere packing, 100 angstrom pore size, 5 µm particle size, and 10% carbon load (Alltech, Deerfield, IL) and a repackable C18 reverse phase guard column (with Alltech Pellicular C18 Refill) were used. The aqueous mobile phase (A) consisted of 0.25 mM tetrabutylammonium phosphate (TBAP, ion-pairing reagent) in water, while the organic phase (B) consisted of 0.25 mM TBAP in 80% acetonitrile. Each phase was brought to pH 3.0 with 10% phosphoric acid. An 18-min gradient was used for metabolite separation and began with 90% A with a flow rate of 1.5 ml per minute and with a column temperature of 40°C. A Shimadzu SIL-6A (Shimadzu, Kyoto, Japan) autosampler delivered injection volumes of 50 µL. The HPLC gradient continued as shown in Table 2.
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hGSTA1 genotyping assay.
Human GSTA1 genotyping was performed as described previously with slight modifications (Coles et al., 2001). The hGSTA1/A2 forward primer AF4 (5'-tgt tga ttg ttt gcc tga aat t-3') and hGSTA1 gene-specific reverse primer AR1 (5'-agg acg gtg aca gcg ttt aac-3') were generously provided by Dr. Brian Coles (NCTR, Jefferson, AR). Control DNA standards representing the various genotypes were available in our laboratory. An approximately 480 bp DNA fragment was amplified using 0.2 µM each of the primers AF4 and AR1. Reactions (50 µl) contained approximately 0.1 mg DNA, 0.2 mM of each dNTP, 5 units AmpliTaq DNA polymerase (Applied Biosystems), 1.5 mM MgCl2 and 1x PCR buffer as supplied with the enzyme (Applied Biosystems). Amplification was started at 95°C followed by 35 cycles of 1 min denaturation at 94°C, 1 min annealing at 62°C and 1 min extension at 72°C. A final 7 min extension at 72°C was performed before cooling the reactions to 4°C. The approximately 480 bp amplification product was digested with Ear 1 and electrophoresed in a 1.5% agarose gel.
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RESULTS |
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MeP O-Demethylation Activities of Cytosolic Fractions Isolated from Human Livers with Known hGSTM1 and hGSTT1 Genotypes
Activities of the ten cytosolic fractions isolated from individual human livers (livers 106, 108, 109, 110, 113, 118, 124, 126, 131, and 134) showed an almost four-fold interindividual variation in GST-mediated O-dealkylation of MeP, ranging from 0.26 to 0.99 nmol/min/mg. Figure 3 shows MeP activities of individual human samples arranged in groups according to the four possible GSTM1 and GSTT1 genotype combinations. Interestingly, the two samples with the highest activities possess the M1+/ T1and M1/ T1+ genotype combinations, suggesting that neither hGSTM1-1 nor hGSTT1-1 are responsible for the majority of MeP activity exhibited by these hepatic cytosolic fractions. Relatively high activity exists both in the absence of hGSTM1-1 and in the absence of hGSTT1-1 protein. In addition, the two samples with both the GSTM1 and GSTT1 genes present (M1+T1+ genotypes) displayed slightly lower activities than the two M1T1samples. These findings indicate that no correlation exists between the GSTM1 and/or GSTT1 genotypes and MeP O-demethylation activities of the cytosolic fractions.
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Enzymatic Capacity of Purified Recombinant GSTs to Dealkylate MeP
In addition to the cytosolic fractions described above, we analyzed a number of purified recombinant cytosolic GSTs belonging to the alpha (human GSTs A1-1 and A2-2, mouse GSTA3-3, rat GSTA5-5), mu (human GSTs M1-1, M2-2, M3-3, M4-4), pi (human GSTP1-1, mouse GSTs P1-1, P2-2), and theta (human GSTT1-1) classes for their capacity to biotransform MeP (Fig. 4). Surprisingly, hGSTT1-1 possessed the highest MeP activity (546 nmol/min/mg), followed by hGSTA1-1 (65.0 nmol/min/mg) and rGSTA5-5 (53.2 nmol/min/mg). In contrast to hGSTA1-1, which shares 95% sequence identity with hGSTA2-2, the MeP O-demethylation activity of the latter was below the detection limit. Human GSTM1-1 also exhibited some capacity to biotransform MeP (10.8 nmol/min/mg), while human and murine pi class GSTs had relatively low activity toward MeP (hGSTP1-1, 2.84 nmol/min/mg, and mGST P1-1, 3.14 nmol/min/mg).
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Since hGSTT1-1 and hGSTA1-1 exhibited the highest activities toward MeP, we attempted to conduct kinetic analyses. However, due to limited solubility, we were not able to reach sufficiently high concentrations of MeP to complete kinetic analysis. At 60, 100, and 300 µM MeP, hGSTA1-1 (at 1 mM glutathione) exhibited MeP O-demethylation activities of 24.4, 39.4, and 65.0 nmol/min/mg, whereas hGSTT1-1 (at 10 mM glutathione) biotransformed MeP at rates of 156, 254, and 874 nmol/min/mg, respectively.
Correlation of Human Liver Cytosolic MeP O-Demethylation Activities with the hGSTA1 Genotype
Recently, Coles and colleagues identified a polymorphism in the proximal promoter region of the human GSTA1 gene (Coles et al., 2001) and named the corresponding allelic variant hGSTA1*B. In addition, they reported that mean levels of hepatic hGSTA1-1 protein expression correlated significantly with genotype (hGSTA1*A > hGSTA1*B). Therefore, we genotyped the ten human liver samples used in this study for hGSTA1*A and hGSTA1*B. Five samples (131, 126, 124, 110, 108) were heterozygous (hGSTA1*AhGSTA1*B), and three samples (118, 109, 106) were homozygous for hGSTA1*A. One sample (113) was homozygous for hGSTA1*B, and the genotype of one sample (134) could not be identified clearly (Fig. 5). Upon comparison of the mean desmethylation activities corresponding to the three hGSTA1 genotypes using ANOVA (p < 0.05), we found no significant differences between groups. Thus, it is unlikely that a correlation exists between hGSTA1 genotype and MeP activity.
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DISCUSSION |
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Of particular interest to us was the relative importance of hGSTM1-1 and hGSTT1-1, for which gene deletions are common in the human population. The lack of any significant correlation between the hGSTM1 and/or hGSTT1 genotypes and MeP dealkylation activities of hepatic human cytosolic fractions suggests that these GSTs do not contribute significantly to total hepatic GST activity toward MeP (Fig. 3). However, caution needs to be exercised in drawing the general conclusion that hGSTM1-1 and hGSTT1-1 play only minor, if any, roles in O-dealkylation of MeP based upon correlational data alone. While it is clear that individuals with hGSTM1 or hGSTT1 null genotypes lack corresponding hGSTM1-1 or hGSTT1-1 protein, it cannot be assumed that all individuals who possess one or two functional alleles for hGSTM1 and/or hGSTT1 express similar amounts of hGSTM1-1 and/or hGSTT1-1 enzymes in hepatic tissue.
One factor that influences enzyme expression levels is the number of alleles present. The assay we used to genotype the ten human samples (Chen et al., 1996) does not distinguish homozygous from heterozygous M1 and/or T1 positive samples and, therefore, does not provide information with respect to the number of GSTM1*A/B or GSTT1*A alleles. In addition, regulation of GST expression is subject to a complex set of developmental, sex, and tissue-specific factors, as well as environmental and dietary parameters (for review see Hayes and Pulford, 1995
). Therefore, it is possible that human livers with a hGSTM1 and/or hGSTT1 positive genotype express varying levels of the encoded proteins. In such a scenario, it is possible that a correlation between hGSTM1 and hGSTT1 genotypes and MeP activity could be masked by other variables that influence the level of protein expression. This is particularly true if the sample size is small, as is the case in our study.
To clarify this issue, we determined MeP activities of several purified recombinant GSTs, including hGSTs M1-1 and T1-1 (Fig. 4). Surprisingly, purified recombinant hGSTT1-1 exhibited the highest specific activity toward MeP. This finding seems contradictory to the lack of correlation between MeP activities displayed by total hepatic cytosolic samples and their corresponding hGSTT1 genotypes. However, if hepatic hGSTT1-1 is expressed at very low levels compared to a GST that possesses significant MeP activity and also is expressed at much higher levels in human liver, this discrepancy would be explained.
When 1 mM glutathione was used in the assay, hGSTA1-1 biotransformed MeP at a rate of 65.0 nmol/min/mg, whereas hGSTT1-1 displayed approximately eight-fold higher activity (545.8 nmol/min/mg) (Fig. 4). Furthermore, given that the Km for glutathione for hGSTT1-1 is approximately 5 mM (versus 0.1 mM for hGSTA1-1 [Meyer, 1993]) and that hepatic concentrations of glutathione are estimated to be 510 mM (Kosower and Kosower, 1978
), a more accurate reflection of the MeP activity of hGSTT1-1 at physiological glutathione concentrations is in the range of 704.8 (measured at 5 mM glutathione) to 874.1 nmol/min/mg (measured at 10 mM glutathione) (Table 3). These activities are approximately 10 to 13-fold higher than that of hGSTA1-1. However, it has been estimated that hGSTA1-1 and hGSTT1-1 account for approximately 23% and 0.003% of total hepatic cytosolic protein, respectively (Meyer et al., 1991
; Rowe et al., 1997
; van Ommen et al., 1990
). Thus, hGSTA1-1 is expressed at approximately 670- to 1000-fold higher levels compared to hGSTT1-1. Taking into account both the differences in O-demethylation activities and hepatic expression levels, we estimate that hGSTA1-1 is responsible for more than 97% of total MeP activity afforded by hGSTA1-1 and hGSTT1-1 combined.
Based on those numbers, one would estimate that MeP activity of hepatic cytosolic fractions would be in the range of 1.3 to 1.9 nmol/min/mg, assuming no other GST contributed to that activity. This estimate is in reasonable agreement with the MeP O-demethylation activity we measured in the ten human cytosolic fractions at a concentration of 1 mM glutathione (range of 0.260.99 nmol/min/mg; Fig. 3), suggesting that hGSTA1-1 is indeed likely responsible for the majority of MeP activity seen in human liver.
As previously stated, hGSTT1-1 has a relatively high Km for glutathione (?5 mM). To ensure that we had not underestimated the contribution of hGSTT1-1 to overall MeP activity in hepatic cytosolic samples by including only 1 mM glutathione, we pooled six samples that were hGSTT1/hGSTM1 positive and measured MeP activity at both 1 mM and 5 mM glutathione. MeP activity of the pooled cytosolic fractions was not significantly different between those two conditions (Student's t-test; p < 0.05) (Table 3). This is a further indication that, in contrast to hGSTA1-1, hGSTT1-1 does not play a major role in MeP O-demethylation activity in the liver. Importantly, however, hGSTT1-1 is expressed in brain and skeletal muscle, which are major target organs for MeP toxicity (Sherratt et al., 1997). Therefore, although hGSTT1-1 does not appear to contribute significantly to hepatic detoxification of MeP in vitro, it could be important in target-tissue biotransformation of MeP. However, whether this is the case in vivo remains to be established.
Interestingly, our finding that hGSTT1-1 biotransforms MeP is consistent with results generated using OP-resistant houseflies. In the resistant insects, the overexpressed GST belongs to the theta class (Zhou and Syvanen, 1997). Recently, a theta class GST was cloned from the housefly; the corresponding purified theta class enzyme biotransformed MeP (Wei et al., 2001
).
Coles and coworkers (2001) reported a polymorphism in the proximal promoter region of hGSTA1-1 that correlated with hepatic expression of hGSTA1-1 protein. We genotyped the ten livers used in this study (Fig. 5), but found no correlation between hGSTA1*A/hGSTA1*B genotypes and MeP dealkylation activities. The lack of correlation could be due to the small sample size used in this study; five of our samples were hGSTA1*A/hGSTA1*B heterozygous, three were hGSTA1*A homozygous, and only one sample was hGSTA1*B homozygous (the genotype of one sample could not be clearly identified). While Coles et al. found a correlation between hGSTA1*A/*B genotypes and hepatic hGSTA1-1 protein levels, they also noted much variation of expression among individuals with the same genotype. Several individuals who were homozygous for hGSTA1*A and hGSTA1*B expressed virtually the same amounts of hGSTA1-1 protein in their livers (Coles et al., 2001
). The hGSTA1*B allelic variant was also identified in an independent study (Bredschneider et al., 2002
). In contrast to Coles et al., Bredschneider and colleagues did not find a correlation between the hGSTA1*A/hGSTA1*B genotypes and hGSTA1-1 protein levels. It is possible that additional, as yet unidentified, factors may also modulate hepatic expression levels of hGSTA1-1 and therefore undermine the effects of the polymorphism. These inductive or suppressive factors may include variation in diet, therapeutic drug use or disease.
Whether GST-mediated biotransformation plays a significant physiological role in MeP disposition in vivo remains to be established. Certain lines of evidence suggest that GST biotransformation of MeP occurs in vivo in rodents. For example, upon pretreatment of mice with diethyl maleate (DEM), glutathione depletion occurs in every tissue examined, including the brain (Costa and Murphy, 1984). This pretreatment also potentiated MeP toxicity (Mirer et al., 1977
; Sultatos and Woods, 1988
). In contrast, several other studies suggest that GST-mediated biotransformation of MeP does not occur in vivo. Rat livers perfused in situ did not demonstrate GST-mediated biotransformation (Zhang and Sultatos, 1991
), and in mouse liver preparations that included microsomes, MeP appeared to be sequestered in the lipid phase and GSH-dependent biotransformation was decreased (Huang and Sultatos, 1993
). In addition, following glutathione depletion by buthionine sulfoximine or acetaminophen in mice, no potentiation of MeP toxicity occurred (Costa and Murphy, 1984
; Sultatos and Woods, 1988
). However, in the case of acetaminophen, glutathione depletion did not occur in the brain, a major target organ for MeP toxicity (Costa and Murphy, 1984
). Furthermore, these could be species-specific observations.
We have shown that human GSTs A1-1 and T1-1 O-dealkylate MeP in vitro. However, whether GSTs play a role in the detoxification of MeP in humans in vivo remains to be determined.
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ACKNOWLEDGMENTS |
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NOTES |
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2 Current address: Department of Molecular Carcinogenesis, MD Anderson Cancer Center, Smithville, TX 78957.
3 To whom correspondence should be addressed. Fax: (206) 685-4696. E-mail: deaton{at}u.washington.edu
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