Journal of Clinical Anesthesia (2015) 27, 73–79

Review Article

Glutathione S-transferase as a toxicity indicatorin general anesthesia: genetics andbiochemical function

Adam Mikstacki MD, PhD (Head of Department of Anesthesiology and Intensive Care)a,Oliwia Zakerska-Banaszak MSc (PhD Student)b,c,Marzena Skrzypczak-Zielinska PhD (Assistant Professor of Human Genetics)d,⁎,Barbara Tamowicz MD, PhD (Consultant of Anesthesiology and Intensive Care)a,Marlena Szalata PhD (Assistant Professor of Biochemistry)c,d,Ryszard Slomski PhD (Professor and Head of Department of Biochemistryand Biotechnology)c,d

aDepartment of Anesthesiology and Intensive Therapy, Regional Hospital, Poznan, PolandbThe NanoBioMedical Centre, Adam Mickiewicz University, Poznan, PolandcDepartment of Biochemistry and Biotechnology, University of Life Sciences, Poznan, PolanddInstitute of Human Genetics, Polish Academy of Sciences in Poznan, Poznan, Poland

Received 24 May 2013; revised 23 July 2014; accepted 25 July 2014

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Keywords:GST;Anesthesia;Genetics;Toxicity

Abstract General anesthesia may lead in patients to unexpected and adverse reactions including toxicity.Glutathione S-transferases (GSTs) are enzymes responsible for the detoxification process of anestheticagents. Plasma and urine GST measurements are used in multiple studies as a hepatocellular integrity orrenal injury indicator. The importance of GST enzyme measurements in monitoring the hepatotoxic andnephrotoxic effect in anesthetized patients is presented. The biochemical function and specific propertiesof GST render it a prognostic biomarker. This review demonstrates that GST can be valuable andpromising toxicity indicator in patients undergoing general anesthesia.© 2014 Elsevier Inc. All rights reserved.

1. Introduction detoxifying activity of GST isoenzymes covers drugs,

The discovery of the detoxifying function of glutathioneS-transferase (GST) marked the beginning of the attempts touse its level and activity measurements as a biomarker. The

⁎ Correspondence: Marzena Skrzypczak-Zielinska, PhD, Institute ofuman Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479oznan, Poland. Tel.: +48 502 459 904; fax: +48 61 848 72 11.

E-mail address: mskrzypczakzielinska@gmail.com. Skrzypczak-Zielinska).

ttp://dx.doi.org/10.1016/j.jclinane.2014.07.002952-8180/© 2014 Elsevier Inc. All rights reserved.

carcinogens, xenobiotics, and other hydrophobic substrates,and thus, it can be treated as a toxicity indicator for manycompounds [1]. Investigations on the GST enzyme respondto the needs of modern anesthesiology. Currently usedanesthetic agents (including propofol and sevoflurane) aregenerally metabolized by the liver. Unexpected and adversereactions in their activity may occur, for example, bradycar-dia (5%-23%), hypotension, ophthalmic or motor disorders,and propofol infusion syndrome [2]. Disturbance of

74 A. Mikstacki et al.

hepatocellular integrity as a result of anesthesia with halothane,enflurane, sevoflurane, desflurane, propofol, and isoflurane wasstudied [3-5]. Serum and urine GST measurements are widelyused in the studies as toxicity indicator of anesthetics in the liverand in the kidney [6-8].

2. Advantages of GST as a marker

GST [EC 2.5.1.18] constitutes a superfamily of solubledimeric isoenzymes, which perform detoxicating, transport-ing, and binding functions. These proteins catalyze theconjugation of an electrophilic substrate to reduced glutathi-one, which facilitates the elimination of exogenous substancesfrom the organism. They also transport substanceswith limitedwater solubility. So far, 8 cytosolic classes of GST enzymeslocated on different chromosomes have been identified inhumans: α, β, δ, ε, θ, μ, π, andω. The GSTs are characterizedby highly homologous amino acid sequence. Each class showsa specific substrate affinity and is encoded by one or severalhighly polymorphic genes [1,9]. Themajor fraction of the GSTenzyme in the human liver is class α, which comprises 65%-80% of its total amount and occurs mainly as the GSTA1-1homodimer. The α-GST enzyme is also present in smalleramounts in the kidneys, testis, adrenal glands, and smallintestine. Apart from biotransformation of a wide range ofexogenous substances, the enzyme is also involved in themetabolism of endogenous substances. Any changes in itslevel and activity in the tissues, serum, and urine are treated as aspecific diagnostic marker. The α-GST protein is a moresensitive marker of hepatocellular integrity than convention-ally analyzed aspartate aminotransferase (AST) and alanineaminotransferase (ALT). This is due to its relatively smallmolecular weight (51 kDa), almost twice lower compared toAST, which allows for a more efficient distribution as well as amore dynamic increase and decrease of the protein level.

The shorter half-life of α-GST (b90 minutes) comparedto ALT makes it possible to precisely determine the hepaticinjury time and monitor the hepatocellular disturbancemechanism [6]. This was proven in the case of, for example,hepatitis, acetaminophen overdose, and halothane anesthesia[10-12]. Increased concentration of α-GST in the serum wasobserved in terms of hepatic inflammation. Its high level inthe urine may indicate renal injury or oxidative stress in thekidneys [13]. Disturbance of hepatocellular integrity leads toa rapid release of the enzyme to the bloodstream, which is avaluable indicator in the toxicity analysis of drugs metab-olized in the liver [14]. Different immunochemical tests forα-GST detection published in the 1980s and commercialenzyme-linked immunosorbent assay kits facilitated theclinical use of α-GST measurements as an indicator ofhepatocellular damage. In the analyses of the renal function,α-GST is a specific marker for the proximal part of thenephron, whereas class π-GST for its distal part [7]. The π-GST fraction is present in the majority of tissues. Therefore,

its increased level may serve as cytotoxicity index of a givensubstance, mainly xenobiotics [15]. It was proved to be relevantin the carcinogenesis and other pathogenic processes.

3. GST measurements in anesthesia

GSTmeasurements became an important element in optimalplanning of anesthesia, both inhaled and intravenous throughmonitoring of the hepatic and renal condition during and afteranesthesia. Disturbance of hepatocellular integrity as a result ofanesthesia with halothane, enflurane, sevoflurane, desflurane,propofol, and isoflurane was shown and described many times[3-5]. Several studies analyzing the liver function indicate theimportance of class α-GST enzyme or its dominating fractioncalled “basic form” (GSTB1), as opposed to the entire moleculeof the GST enzyme.

Investigations of halothane anesthesia from 1986 havereported a 2-fold temporary increase of GST B1 and B2enzyme levels in the serum of patients: 1-3 hours and24 hours after anesthesia [12]. The first increase was ascribedto the hepatotoxic activity of halothane itself, whereas thesecond one was caused by the activity of its metabolites.GST level measurement demonstrated more efficient thanthe ALT level analysis, which did not show any significantchanges. Two years later, GST B1 was used to compare thehepatotoxic activity of halothane, enflurane, and isoflurane.However, only isoflurane did not cause any significantincrease of the enzyme level in the serum after anesthesia[16]. Tiainen and Rosenberg [17] measured the entire serumα-GST fraction to compare the hepatocellular integrity afteranesthesia with halothane and isoflurane. As opposed to theprevious study, they observed a slight rise of the GSTenzyme concentration in both anesthetics, which indicatedtheir mild hepatotoxicity. The differences in the results maystem from the anesthetic conditions and group of patients aswell as the sensitivity of the enzymatic tests.

Tiainen et al excluded factors such as blood pressuredecrease, anesthesia time, surgery type, age, sex, or bodymass index as having influence on the increase of the α-GSTlevel. Moreover, it was observed that, in women, the level ofthe entire α-GST fraction was higher in the liver and lower inthe serum as compared with men. GST enzyme was shown tobe an indicator of induced hepatotoxicity also in the case ofdesflurane, isoflurane, and enflurane [4,18]. Several inves-tigations on propofol conducted with the use of GSTdemonstrate a lower toxicity of this intravenous anestheticcompared to inhaled anesthetic agents [19,20]. In vitrostudies show that propofol in the concentration less than1.0 mmol/L does not inhibit the activity of this protein.

Measurements of GST as a sensitive indicator of the livercondition were also used to assess the safety of anesthesia innonstandard conditions. The effect of prolonged propofolinfusion (approximately 10 hours) on the liver condition wasanalyzed. No significant changes of the GST level in the serum

75GST isoenzymes in anesthesia

were observed [21]. Similarly, prolonged isoflurane anesthesiadid not cause any differences in the levels of GST B1 and B2 inthe liver [22].General anesthesiawith sevoflurane and halothaneadministered to children as well as with desflurane andsevoflurane low flows in elderly patients resulted in the increaseof the α-GST concentration in the serum, which returned tonormal within 24 hours [23,24]. Higher sensitivity of α-GST asa hepatic indicator, compared with aminotransferases (ALT andAST), was also shown by Yousif et al [25] in his studies onsevoflurane in a group of patients with induced hypotension andwithout hypotension. Serum α-GST level increased in bothanesthetized groups after 1 hour, and hypotension enhanced thiseffect. The level ofπ-GST,ALT, andAST remained unchanged.

Moreover, GST level measurements were used in theanalysis of particular substances' impact, for example, nicardy-pine, cimetidine, and N-acetylcysteine, on the toxicity of theinhaled anesthetic agents [26-28]. Administration of nicardipinebefore and during halothane anesthesia was used to test thepossibility of decreasing the GST enzyme level released fromhepatocytes. Based on the GST B1 fraction analysis, it wasdisplayed that nicardipine did not have a protective function[26]. Similarly, cimetidine administered before anesthesia didnot cause the increase of GST in the serum of the patientsanesthetized with halothane [27].

Beside the assessment of the integrity of hepatocytes, whichare most exposed to the toxic effect of anesthetic agents, theirnegative impact on kidneys is also analyzed. In this case in urine,levels of α-GST fraction, which is specific for the proximal partof the nephron and π-GST typical for its distal part, aremonitored. Comparative analysis of nephrotoxic impact ofsevoflurane and desflurane reveals that only sevoflurane causedincrease of bothα-GST andπ-GST levels. This result correlatedwith the ALT value, and it confirms the transient adverse impactof the anesthetic on the functioning of the renal tubule [7]. Thebreakdown of sevoflurane during its reaction with CO2

absorbents results in the formation of vinyl ether, which istoxic. Thus, the following studies included analyses of the toxicinfluence of sevoflurane, isoflurane, and vinyl ether dependingon their dose as well as α-GST levels, and other biochemicalparameters were used as markers. The renal parameters wereaffected by vinyl ether rather than sevoflurane [29]. Renaleffects of combined anesthesia involving ketorolac andsevoflurane were also assessed by means of analysing α-GSTand π-GST levels as specific indicators of proximal and distalnephron functions [30]. Measurements of GST showed that theuse of ketorolac did not result in clinically significant changes inrenal glomerular or tubular function in the anesthetized group.The α-GST parameter is used in studies not only as a specificindicator for the proximal part of the nephron but also as amarker of nephrotoxicity of nonorganic fluorides released as aresult of sevoflurane biotransformation [31].

Studies describing conditions of increased risk also belong tothe wide group of investigations focused on renal side effects ofsevoflurane. The level of GST as an indicator of changesdepends on a number of factors involving the time of exposureto an anesthetic agent and its flow rate, the group of anesthetized

patients, their age, renal dysfunctions, cardiac diseases, andobesity. Genetic studies suggest that the level of GST enzymesmay also be affected by the polymorphism of genes coding forthese proteins.

4. Genetic variability of GST enzymes

Genetic information responsible for the synthesis of cytosolicGSTs is located on 7 separate chromosomes. Each class is mostoften coded by a group of genes [32]. The classesα-GST andπ-GST are particularly prognostic in anesthesia monitoring. Manyscientists focus on the variability of genes coding for these 2fractions of the enzyme.

Human α-GST is a product of DNA fragments, which areexpressed in different tissues. The enzyme occurs mainly inthe liver as a GSTA1-1 homodimer. Five functional genes(GSTA1-5) and 7 pseudogenes have been identified in thisclass on chromosome 6. Human α-GST 1 (hGSTA1) genecoding for the main subunit, GSTA1, was described ashighly polymorphic. The discovered genetic variants deter-mine individual susceptibility to cancer-causing substancesand toxins. Moreover, they affect the toxicity and efficacy ofmany drugs by interacting with gene expression [8].

Several studies point out that polymorphism of the promoterregion has the main influence on the expression of the hGSTA1gene in the liver. It is characterized by 2 alleles hGSTA1*A andhGSTA1*B, which are defined by 3 associated substitutions:−567 T N G, −69C N T, −52G N A. Nucleotide change in theposition −52 is known to be responsible for diverse promoteractivity of the gene resulting in the disturbance of binding theSp1 transcription factor. In effect, hGSTA1*B homozygotesexhibit lower gene expression in the liver [33]. Coles et al [33] infurther studies demonstrated that the occurrence of −69C N T,−52G N A decreases the enzyme activity 4-fold, whereas thenext variant −115A, 5-fold.

Decreased enzymatic activity of the hGSTA1*B haplotypewas also found in theChinese population [34]. Polymorphism ofhGSTA1 gene in thewhite population, especially in the promoterregion, was showed by the sequence analysis of the coding partof the gene together with the promoter region [35]. Seven singlenucleotide polymorphisms were localized: −52G N A, −69C NT, −513A N G, −567 T N G, −631G N T, −1066 T N A, and−1142G N C, where the frequency of 3 main sequencevariationswas 47.9%.The coding regionwas found to have only1 substitution, 375A N G, which is located in exon 5. Althoughnone of the polymorphisms exhibited a correlationwith the leveland activity of the GST protein in the liver in the presence ofbusulfan, these variants remain subject of important research.

hGSTA1 gene is closely related to the second alpha classgene, hGSTA2, which is known to have 5 alleles—GSTA2*Ato *E. These alleles differ in variants located in exons 5-7:GSTA2*A (Pro110, Ser112, Lys196, Glu210), GSTA2*B(Pro110, Ser112, Lys196, Ala210),GSTA2*C (Pro110, Thr112,Lys196, Glu210), GSTA2*D (Pro110, Ser112, Asn196,

76 A. Mikstacki et al.

Ala210), and GSTA2*E (Ser110Ser112Lys196Glu210).Maekawa et al [36] detected genetic variations of both genesin patients with colorectal cancer receiving chemotherapy, whenlooking for haplotype structures. He found haplotype combina-tions of both genes: GSTA1*A-GSTA2*C, GSTA1*A-GSTA2*B, and GSTA1*B-GSTA2*E. These results can beuseful in pharmacogenomic and toxicity studies [36].

Genetic variability of π-GST is associated with thepolymorphic character of human GST pi 1 gene (hGSTP1)located on chromosome 11. Three polymorphic forms of thehGSTP1 gene have been identified: GSTP1*A, GSTP1*B, andGSTP1*C. Allele GSTP1*A is defined by isoleucine (Ile) atcodon 105 and alanine (Ala) at codon 114, allele *B by changeIle105Val, whereas allele *C is defined by 2 amino acidvariations: Ile105Val and Ala114Val [37]. Both amino acidsubstitutions in codons 105 and 114 are located in the activecenter of the enzyme, where electrophilic substrates are bound. Itis crucial for the enzymatic activity of this protein. These changesresult in a 4-fold decrease of catalytic activity of the enzyme, sothey contribute to the impairment of the protective mechanismagainst oxidative stress and ineffective detoxification [38]. Thesepolymorphisms were studied extensively for various substancesand diseases including the metabolism of acetaminophen,Parkinson disease, and cancer. Pioneering investigations onassociation of the hGSTP1 genetic variability and the toxicityindicator in anesthesiawere performedbyKaymak et al [39]. Theresults demonstrated a correlation between the Ile105Valpolymorphism in hGSTP1 gene and mild hepatotoxicity inpatients undergoing general anesthesia with sevoflurane.

The Ile105Val substitution, contrary to Ala114Val, signifi-cantly reduces the activity of the protein in lungs in the whitepopulation [40]. A similar conclusion was formulated for theIle105Val polymorphism in the Chinese population based onstudies of π-GST activity in erythrocytes [41]. It was verifiedthat a substitution in codon 105 is more frequently observed inwhite and African populations (42%), than in the Asianpopulation (33%) [40]. Moreover, it was confirmed that thehGSTP1 rs1695 variant is associated with the increased risk ofside effects because of the reduced busulfan clearance [42]. Thestudy on predictive polymorphism for prognosis of osteosarco-ma patients receiving chemotherapy shows that individualscarrying genotype hGSTP1 Val105Val live shorter than thosewith the Ile105Ile variant [43].

The analysis of correlation between different variants ofthe GST genes, GST activity, and response to drug treatmentis of significant importance for the development oftoxicology, chemotherapy, and determination of risk levelsof numerous diseases.

5. Potential of GST genetics in prognosingsafe anesthesia

Complex environmental factors are not the only cause ofindividual variability of the GST enzyme activity. Research hasrevealed that genetic variants of GST translate into phenotypic

effects. The presence of certain changes and mutations at thelevel of DNAorRNAmay cause a profoundmodification of thecatalytic activity of the enzyme. Numerous genes from the GSTfamily have not been fully explored yet. The most importantones have become subject of several studies aiming at predictingthe toxic effects of drugs and treatment effectiveness.Investigators focus on searching for associations betweencertain polymorphisms and the occurrence of important diseasesand toxicity of various substances. It is known that a very lowlevel of GST activity is related to increased risk of lung, breast,andmouth cavity tumors aswell as inflammatory diseases such asasthma and rheumatoid arthritis. Patients with high GST activityare resistant to chemotherapy [41]. Moreover, inhibition of GSTS1-1 activity is important in antiallergy and anti-inflammationactions because the enzyme is responsible for production ofmediator of allergy and inflammation responses [44].

Multiple studies investigate the variability of π-GST and α-GST levels as indicators of kidney and liver dysfunction inpatients subjected to anesthesia (Table 1).However, there are fewstudies that would additionally include the genetic variability inthese analyses. Kaymak et al [39] attempted to find a correlationbetween the hGSTP1 polymorphism and the level of the α-GSTenzyme in the serum of patients anesthetized with sevoflurane.The Ile105Val variant of the hGSTP1 gene is responsible formaintaining a high level of the enzyme in the serum after24 hours from anesthesia, yet the choice of gene subjected toanalysis is quite astonishing. Changes in the hGSTA1 gene affectthe synthesis of α-GST, and changes in the hGSTP1 gene affectthe process of π-GST enzyme formation. The plan of theconducted study is ambiguous, but it is a fact that adjustingthe conditions of anesthesia for individual patients including thegenetic factors is reasonable. Koumaravelou et al [45] underlinethe need of further research in this area and development ofsimple and repeatable methodology for GST measurement.

6. Conclusions

Multiple studies confirm the usefulness of the GST enzyme asa toxicity indicator in general anesthesia, but little is known aboutthe associations of the level of this enzyme with its geneticvariability. Different polymorphisms of GST genes seem toinfluence the enzyme efficiency and the response to anestheticdrugs. Combining the levels of α-GST and π-GST toxicityindicators with the sequence analysis of key genes coding forthese proteins may be prognostic. It would allow effective andsafe planning of anesthesia adapted to the genetic profile of thepatient by choosing dosage and type of anesthetics as well asadditional drugs adjusted to the enzymatic activity.

Acknowledgments

This work was supported by the Polish Ministry of Scienceand Higher Education (grant no. N N401 037838). Oliwia

Table 1 The GST enzymes as a biomarker in toxicity investigations on different anesthetic agents

Analyzedanestheticagent

Fraction ofmeasured GSTenzyme

ObservedpostanestheticGST level change

Additionallyanalyzedmarkers

Observed postanestheticlevel change inadditional markers

Type of observeddisturbance

Reference

Halothane Serum GSTB1

↑ ALT No Hepatotoxicity 12

Serum GSTB2

↑

Halothane Serum GSTB1

↑ ALT, ALP,GGT

No Impairment of hepatocellularintegrity

16Enflurane ↑ NoIsoflurane No No NoneHalothane Serum α-GST ↑ ALT ↑ Mild hepatotoxicity 17Isoflurane ↑ NoDesflurane Serum α-GST ↑ ALT, AST No Impairment of hepatocellular

integrity4

Isoflurane ↑ NoDesflurane Serum GST No ALT, AST No None 18Enflurane ↑ No Hepatocellular injuryDesflurane Serum α-GST ↑ ALT, AST No Impairment of hepatocellular

integrity19

Propofol No No NoneDesflurane Plasma α-GST ↑ ALT, AST No Impairment of hepatocellular

integrity20

Propofol No No NoneSevoflurane Serum α-GST ↑ ALT, AST,

HANo Impairment of hepatocellular

integrity25

Serum π-GST No ↑ (patients withinduced hypotension)

Propofol Serum GST No None No None 21Isoflurane Plasma GST

B1No None No None 22

Plasma GSTB2

No

Propofol Plasma GSTB1

No

Plasma GSTB2

No

Sevoflurane Serum α-GST ↑ ALT, AST,ALP

No Mild impairment of hepatocellularintegrity

23Halothane ↑ NoDesflurane Serum α-GST ↑ ALT, AST,

GGTNo Minimally affected hepatic

integrity24

Sevoflurane ↑ NoSevoflurane Urine α-GST ↑ Urinary

albumin↑ Dose-related renal injury

Hepatocellular injury—notobserved

7

Glucose ↑BUN No

Urine π-GST ↑ Serumcreatinine

No

ALT NoDesflurane Urine α-GST No Urinary

albuminNo none

Glucose NoBUN No

Urine π-GST No Serumcreatinine

No

ALT NoSevofluranemetabolite—vinyl ether

Urine α-GST ↑ Urinaryalbumin

↑ Dose-related transient renalinjury

29

GlucoseSevoflurane Serum α-GST ↑ None No Genotype-related hepatocellular

injury39

ALP = alkaline phosphatase; GGT = γ-glutamyl transpeptidase; HA = hyaluronic acid; BUN = blood urea nitrogen.

77GST isoenzymes in anesthesia

78 A. Mikstacki et al.

Zakerska-Banaszak receives a doctoral scholarship from TheEuropean Regional Development Found and European Foundfor Innovative Economy and Foundation for Polish Science(Warsaw). She is also a scholarship holder within the project“Scholarship support for PhD students specializing in majorsstrategic for Wielkopolska's development,” Sub-measure8.2.2 Human Capital Operational Programme, cofinanced byEuropean Union under the European Social Fund (Poznan).

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