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Variability of Glutathione S-transferase [alpha] in human liver and plasma.

Cytosolic glutathione S-transferases (GSTs; [1] EC are enzymes that catalyze the nucleophilic addition of glutathione to the electrophilic centers of a wide variety of chemical structures. In addition, GSTs exert part of the glutathione peroxidase activity and have an important function in intracellular binding and transport of a wide variety of both endogenous and exogenous compounds (1, 2). The family of human enzymes is divided into four main classes: [alpha], [mu], [pi], and [theta], each subdivided into one or more isoenzymes (1-3).

Glutathione S-transferase [alpha] (GST-[alpha]) is found at high concentrations in the human liver and is released quickly and in large quantities into the bloodstream during hepatocellular damage (4). Because the half-life of GST-[alpha] in plasma is ~1 h (5), its concentration will follow changes in hepatocellular damage more rapidly than aspartate aminotransferase (AST; EC or alanine aminotransferase (ALT; EC, which have plasma half-lives of ~17 and 47 h, respectively (4).

[1] GSTs are dimeric enzymes, and the GST-[alpha] class comprises two immunologically distinct subunits, GSTA1 and GSTA2, which are encoded by separate genes (6, 7). Two homodimers, GSTA1-1 and GSTA2-2, and the heterodimer GSTA1-2 have been purified from human liver (7).

Several immunochemical assays for GST-[alpha] were published in the 1980s (8-14); recently, however, several sensitive and specific ELISAs have been developed in different laboratories (15-17). The introduction of a commercial ELISA kit [Hepkit; Biotrin International; Ref. (18)] has facilitated the clinical application of GST-[alpha] as a marker for hepatocellular damage. Recent studies demonstrated that measurement of serum or plasma GST-[alpha] may improve the monitoring of hepatocellular integrity in patients with hepatitis C (19, 20), in anesthetized patients (21), in liver transplant recipients (22-24), and in women with severe preeclampsia (25, 26).

In several studies, reference values for plasma or serum GST-[alpha] in healthy controls were reported (8-15, 18); however, Tiainen and Karhi (16) were the first to notice that males had significantly higher plasma GST-[alpha] concentrations than females. Recently, in a larger study on the plasma GSTA1-1 concentrations of blood donors, we obtained similar results and also noticed a significant increase of plasma GSTA1-1 with increasing age in females but not in males (17).

Little is known about GST-[alpha] isoenzyme composition in human liver with respect to gender and age. Corrigall and Kirsch (27) reported on the concentration of GST-[alpha] in livers from nine male subjects. Strange et al. (28) and Van Ommen et al. (29) measured GSTA1 and GSTA2 in 20 human liver specimens, but no information on gender and age of the subjects included in these studies was available.

We developed several monoclonal antibodies against GST-[alpha]: one antibody recognizes GSTA1-1 and GSTA2-2 as well as GSTA1-2 (30), whereas another antibody is specific for GSTA1-1 (17). Two sandwich ELISAs based on these monoclonal antibodies were developed, and these assays were used for measuring both GSTA1-1 and total GST-[alpha] in liver cytosols from 35 organ donors and in blood plasma from 350 healthy blood donors.

Materials and Methods

Chemicals were analytical grade and were obtained from Sigma Chemical Co., unless stated otherwise.


GST-[alpha] was purified from human liver (31) and contained ~40% GSTA1-1. Highly purified GSTA1-1, GSTA1-2, and GSTA2-2 were a generous gift from Dr. P.J. van Bladeren, TNO Nutrition, Zeist, The Netherlands.

Production and characterization of the specific monoclonal antibodies against GST-[alpha] and GSTA1-1 were described previously (17, 30). A polyclonal antiserum was prepared as follows: rabbits were immunized by intracutaneous injection of 100 [micro]g of total GST-[alpha] in complete Freund's adjuvant and boosted twice by subcutaneous injection of 50 [micro]g of GST-[alpha] in incomplete Freund's adjuvant.

IgG was purified using Protein A Sepharose CL-4B, according to the manufacturer's instructions (Pharmacia).


Assays for total GST-[alpha] and GSTA1-1 were performed in 96-well polystyrene plates (Greiner). All incubations were done at room temperature in 100 [micro]L/well, unless stated otherwise. Between incubations, plates were washed five times with >200 [micro]L/well phosphate-buffered saline (PBS) supplemented with 0.5 mL/L Tween 20 detergent (PBS-T). Plates were coated overnight at 4[degrees]C with 10 mg/L purified monoclonal antibody in PBS and blocked for 1 h with 200 [micro]L/well PBS-T supplemented with 10 g/L bovine serum albumin (BSA). Calibrators (0.04-20 [micro]g/L GSTA1-1 or 0.2-50.0 [micro]g/L GST-[alpha]), diluted in PBS-T supplemented with 10 mmol/L EDTA and 100 mL/L normal human plasma that had been heated to 60[degrees]C for 30 min, and plasma samples diluted with an equal volume of PBS-T-EDTA-normal human plasma were then added to the wells. Plates were incubated overnight, washed, incubated with rabbit GST-[alpha] antiserum diluted 1:4000 in PBS-T-BSA for 3 h, washed, and subsequently incubated for 2 h with peroxidase-labeled swine anti-rabbit (Dako) diluted 1:2000 in PBS-T-BSA. After a final wash, plates were stained with o-phenylenediamine/ [H.sub.2][O.sub.2]. The absorbance was read at 492 nm with a background subtraction at 620 nm. All calibrators and samples were measured in duplicate. A four-parameter weighted logistic regression model was used to calculate calibration curves and unknowns.

Within- and between-assay coefficients of variation (CVs; SD/mean x 100%) for the total GST-[alpha] assay were calculated from five measurements of 16 plasma samples containing between 1.0 and 43.8 [micro]g/L GST-[alpha]. Analytical recoveries of this assay were determined by the addition of 0.8, 1.6, 3.1, 6.2, 12.5, and 25.0 [micro]g/L GST-[alpha] to plasma samples from 10 healthy controls.

The GSTA1-1 ELISA showed 7% and 0.1% cross-reactivity with GSTA1-2 and GSTA2-2, respectively, and did not cross-react at all with GSTP1-1 and GSTM1-1 (17). Additional characteristics of the GSTA1-1 assay were described previously (17).


Liver cytosols were obtained from the International Institute for the Advancement of Medicine (Exton, PA). Liver cytosols from subjects with a history of diabetes or recent corticosteroid use were excluded from the study.

Thirty-five liver cytosols from organ donors were studied, 19 males (median age, 36 years; range, 16-66 years) and 16 females (median age, 41 years; range, 18-60 years). Twenty-nine of these organ donors were eligible with respect to smoking habits, alcohol consumption, and use of drugs or medication. These data are given in Table 1.

Blood from 350 healthy blood donors was collected at the Red Cross Blood Bank, Nijmegen, The Netherlands, in tubes containing [K.sub.3] EDTA (Becton and Dickinson) and centrifuged at 2000g for 10 min within 2 h after collection. Plasma samples were stored at -20[degrees]C.


Protein concentrations in liver cytosols were determined according to Lowry et al. (32). The GST concentrations in calibrator preparations were quantified using a Bio-Rad protein assay (Bio-Rad Laboratories) because GSTs tend to give spuriously high results in the Lowry protein assay. In both protein assays, BSA calibration curves were used.

Plasma and liver cytosolic AST and ALT activities were measured at the local laboratory for clinical chemistry on a Hitachi 747 analyzer.

To evaluate the significance of differences between groups, the Mann-Whitney U-test was used. Correlations between different assays were evaluated using the Pearson linear correlation procedure. Statistical calculations were done using SPSS/PC+, Ver. 5.01, computer software.

This study was approved by the local Medical Ethical Review Committee.



GSTA1-1, GSTA1-2, and GSTA2-2 gave identical calibration curves in the total GST-[alpha] assay, and the crossreactivity with GST-[pi] and GST-[mu] class proteins was <0.1%. The detection limit, corresponding to 3 SD above the mean signal of five zero calibrators in duplicate, was 0.2 [micro]g/L. Recoveries in plasma samples supplemented with GST-[alpha] ranged from 90% to 118% (mean, 104%), and the mean within- and between-assay CVs were 3.5% and 5.3%, respectively.


Plasma total GST-[alpha] concentrations in 350 healthy controls displayed a skewed distribution, which could be nearly normalized by logarithmic transformation. On the logarithmic scale, the mean value was 2.4 [micro]g/L and the reference range (mean [+ or -] 2 SD) was 0.4 -13.7 [micro]g/L GST-[alpha]. Using the previously published data on GSTA1-1 plasma concentrations (17), we calculated the median ratio GSTA1-1/total GST-[alpha] as 0.58 (0.08 -1.63). Males in the age groups 20-40 years and 40-60 years had significantly (P <0.0002) higher plasma total GST-[alpha] concentrations than females in the same age groups (Table 2). Plasma total GST-[alpha] concentrations increased significantly with age in females (P <0.005) but not in males. Plasma total GST-[alpha] values correlated significantly with plasma GSTA1-1 concentrations (r = 0.87; P <0.0001; Fig. 1).



Total GST-[alpha] and GSTA1-1 concentrations in 35 liver cytosols displayed a nearly gaussian distribution, and the mean concentrations of GSTA1-1 and total GST-[alpha] were 10.7 [+ or -] 5.3 and 25.1 [+ or -] 9.4 [micro]g/mg cytosolic protein, respectively. The concentrations of GSTA1-1 correlated significantly with those of total GST-[alpha] (r = 0.82; P <0.0001; Fig. 2). The mean ratio GSTA1-1/total GST-[alpha] was 0.42 [+ or -] 0.10, indicating that between 22% and 62% (mean [+ or -] 2 SD) of total GST-[alpha] in liver is GSTA1-1. The GSTA1-1 and total GST-[alpha] concentrations in liver cytosols were not correlated significantly with AST (r = -0.11, P = 0.51; and r = -0.27; P = 0.12, respectively) or ALT activities (r = 0.05; P = 0.78; and r = 0.06; P = 0.72, respectively).


The mean total GST-[alpha] concentration in liver cytosols from females was significantly higher than that in males (28.8 [+ or -] 10.0 mg/mg protein vs 22.0 [+ or -] 7.8 [micro]g/mg protein, respectively; P = 0.024). The mean hepatic GSTA1-1 concentration was also higher in females (12.2 [+ or -] 5.6 [micro]g/mg protein vs 9.5 [+ or -] 4.7 [micro]g/mg protein in males), but the statistical significance of difference was only borderline (P = 0.055). In contrast, the mean ALT activity was significantly lower in liver cytosols from females (324 [+ or -] 111 U/mg protein vs 500 [+ or -] 128 U/mg protein in males; P <0.001). Hepatic AST activities were similar in females and males (1410 [+ or -] 618 U/mg protein vs 1394 [+ or -] 444 U/mg protein; P = 0.39).

The hepatic mean CVs (SD/mean) for total GST-[alpha] and GSTA1-1 were 0.38 and 0.49, respectively. The mean CVs for AST (1401 [+ or -] 522 U/mg protein) and ALT activities (420 [+ or -] 149 U/mg protein) were 0.37 and 0.35, respectively.


To date, the immunoassays for total GST-[alpha] published have been based on polyclonal antibodies. As pointed out by Beckett and Hayes (4), antisera from animals immunized with total GST-[alpha] may vary in their cross-reactivity toward the isoforms GSTA1-1, GSTA2-2, and GSTA1-2. Therefore, it could be important to use an antiserum that recognizes only one of the isoforms or, alternatively, to use an antiserum that recognizes all isoforms with equal affinity. We developed a specific assay for GSTA1-1 as well as an assay measuring all GST-[alpha] isoforms. Each assay is based on a specific monoclonal antibody as coating (catching) antibody, but both assays use the same polyclonal detecting antibody that recognizes all GST-[alpha] isoforms with similar affinity.

The great variety in GSTA1-1/total GST-[alpha] ratios demonstrated a large interindividual variation both in liver cytosols and in plasma samples; however, within a group of controls, GSTA1-1 and GST-[alpha] displayed a very significant linear correlation. This highly linear correlation indicates that variations in cross-reactivity of polyclonal antisera toward the different GST-[alpha] isoforms may be of little relevance when groups of patients or controls are compared, at least as long as the assay is based upon the same batch of antibodies. However, when different batches of polyclonal antibodies are used within the same assay format, variations in the cross-reactivity to GST-[alpha] isoforms may have a significant effect upon the GST-[alpha] concentrations measured in plasma or tissue samples.

On the basis of theoretical considerations (very high hepatic concentration, uniform hepatic distribution, and short plasma half-life), the measurement of plasma GST-[alpha] may provide a more sensitive and specific indicator of acute hepatocellular damage than the aminotransferases AST and ALT (4). Many studies evaluating the merits of assaying serum or plasma GST-[alpha] have been published (8-18). However, data on total GST-[alpha] concentrations in human liver are scarce. Corrigall and Kirsch (27) reported a mean total GST-[alpha] of 23.8 [+ or -] 6.1 [micro]g/mg cytosolic protein in livers from nine male subjects. These data are in excellent agreement with the value of 22.0 [+ or -] 7.8 [micro]g/mg protein for males reported here. Strange et al. (28) reported mean GSTA1 and GSTA2 of 12.8 [+ or -] 5.6 and 3.7 [+ or -] 2.1 [micro]g/mg cytosolic protein, respectively, for 20 human liver specimens. Van Ommen et al. (29) also studied 20 human liver specimens, using an HPLC method and reported mean GSTA1 and GSTA2 concentrations of 20.3 [+ or -] 9.0 and 10.7 [+ or -] 8.2 mg/mg cytosolic protein, respectively. The concentrations of GSTA1-1 (10.7 [+ or -] 5.3 [micro]g/mg cytosolic protein) we measured by ELISA are lower, but the total GST-[alpha] values (25.1 6 9.4 [micro]g/mg protein) are comparable to these earlier data. The studies by Strange et al. (28) and van Ommen et al. (29) provided no information on gender and age of the organ donors, whereas we now demonstrate that livers from females contain significantly higher concentrations of total GST-[alpha] than livers from males. These higher hepatic concentrations in females cannot be explained by induction of GSTs by smoking or the use of medicaments because intake in females was lower than in males.

Several studies on GST-[alpha] in human blood plasma, including those using the commercial Hepkit, did not mention an influence of gender on plasma GST-[alpha] (8-15, 18). Tiainen and Karhi (16) reported that males had significantly higher plasma GST-[alpha] concentrations than females, which was confirmed by us for GSTA1-1 previously (17) and in this study for total GST-[alpha]. We hypothesized that the higher plasma concentrations found in males were associated with higher concentrations of GST-[alpha] in male livers (17), based on the assumption that GST-[alpha] in plasma originates mainly from normal hepatocellular turnover. However, the present data show the opposite. One possible explanation for the apparent paradox of low hepatic and high plasma GST-[alpha] concentrations could be that males have a higher hepatocellular turnover than females. Estimation of hepatic contents of ALT, however, did not support this hypothesis because we found significantly lower ALT activity in the liver cytosols of females, whereas the plasma ALT activity is not different between sexes (33). The combination of high hepatocellular and low plasma concentrations of GST-[alpha] in women may therefore be explained by a more rapid plasma clearance of GST-[alpha] in females, but no information on this aspect is currently available.

This work was supported by a grant from the Dutch Cancer Society (NUKC 92-33).

Received August 3, 1998; accepted December 28, 1998.


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[1] Nonstandard abbreviations: GST, glutathione S-transferase; GST-[alpha], glutathione S-transferase a; AST, aspartate aminotransferase; ALT, alanine aminotransferase; PBS, phosphate-buffered saline; PBS-T, phosphate-buffered saline supplemented with Tween 20; and BSA, bovine serum albumin.

THEO P.J. MULDER, DANIEL A. COURT, AND WILBERT H.M. PETERS * Department of Gastroenterology, University Hospital St. Radboud, 6500 HB Nijmegen, The Netherlands.

* Address correspondence to this author at: Department of Gastroenterology, University Hospital St. Radboud, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Fax 31-243540103; e-mail
Table 1. History of drug abuse, smoking, drinking, and use
of medication by the organ donors.

 Males (n = 14) (a) Females (n = 15) (a)

Alcohol consumption 64 (b) 20 (b)
Smoking 50 33
Use of cocaine 21 13
Medication used (c)
 Dopamine 86 66
 Dilantin 14 27
 Solu-Medrol 43 13
 Ancef 57 40
 Mannitol 36 47
 Pitressin 43 20
 Lasix 43 33
 Decadron 21 27

(a) Twenty-nine (14 males and 15 females) of the 35 organ donors
included in this study were eligible with respect to use of
medication, drug abuse, and smoking and drinking habits.

(b) Data are given as percentage of total number of subjects that
could be evaluated.

(c) Only medications that were used by five or more organ donors
are listed.

Table 2. Plasma total GST-[alpha] concentrations in healthy
controls, according to gender and age.

 GST-[alpha], median (range), [micro]g/L

 Age Males Females All

20-40 2.6 (0.4-20.4) 1.8 (0.2-12.0) (a) 2.4 (0.2-20.4)
years (n = 70) (n = 83) (n = 153)

40-60 3.4 (0.2-14.4) 2.0 (0.2-9.2) (b) 2.6 (0.2-14.4)
years (n = 60) (n = 57) (n = 117)

>60 2.8 (0.2-13.0) 3.4 (0.2-14.4) (c) 2.8 (0.2-14.4)
years (n = 45) (n = 33) (n = 78)

All 2.8 (0.2-20.4) 2.0 (0.2-14.4) (d,e) 2.6 (0.2-20.4) (e)
ages (n = 175) (n = 175) (n = 350)

(a) P <0.0002 vs males 20-40 years.

(b) P <0.0001 vs males 40-60 years.

(c) P <0.002 vs females 20-40 years, and P <0.005 vs females
40-60 years.

(d) P <0.0001 vs males, all ages.

(e) Age of two females was not recorded, and therefore numbers
do not add up.
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Title Annotation:Enzymes and Protein Markers
Author:Mulder, Theo P.J.; Court, Daniel A.; Peters, Wilbert H.M.
Publication:Clinical Chemistry
Date:Mar 1, 1999
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