Glutathione S Transferase Elimination Reactive Metabolites From Body Biology Essay

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Glutathione S-transferase 1 (GSTM1) belongs to the GST phase II metabolic enzyme family. It plays an important role in the elimination of reactive metabolites from the body [1]. The µ class enzymes of GST family are involved in the detoxification of active compounds including carcinogens, toxins, electrophilic compounds, drug metabolites and even stress caused by reactive oxygen groups. The detoxification involves simple conjugation of the reactive metabolite with glutathione [2]. GSTM1 alleles encode enzymes that can be categorized into GSTM*0, GSTM*A and GSTM*B respectively. The wild type GSTM1 encodes for the GSTM*A enzyme which is active. A SNP in exon 7 gives rise to the enzyme variant GSTM*B. A deletion polymorphism on the other hand forms the variant GSTM1*0 [6].

ASK1 is an apoptosis signal regulating protein kinase that plays an important role in stress induced apoptosis. The level of activity of this kinase is less when there is no stress on cells. When there is no stress the Ask1 is bound to GSTM1 (Fig.3). In the event of stress the GSTM1 and Ask1 part and Ask1 further activates kinase pathways. Therefore it can be inferred that GSTM1 plays a regulatory role in heat shock induced apoptosis [9, 10, 11, 22].

The homozygous GSTM1 genotype is called the null genotype represented as GSTM1 (-/-). The Heterozygous type is constituted by GSTM1 (+/-) and wild type of homozygous by GSTM1 (+/+) respectively [6]. Nearly 50% of the population has homozygous GSTM1 null genotype. Since the enzyme product is not encoded they are at risk of carcinogenesis [16, 18]. The allelic variants GSTM1*A and GSTM1*B have similar activity towards the substrates [18]. GSTM1*A and GSTM1*B are considered to be positive conjugator phenotypes [41].

5.2 Interaction Mechanism:

A deficiency in GSTM1 enzyme expression results in rise of susceptibility to formation of carcinogen-DNA adducts and damage to the DNA [18]. Carcinogens such as Benzo[a]pyrene (fig.4) move across the plasma membrane through diffusion. The phase I CYP family enzymes are involved in converting the substrate to an epoxide and further to a diol-epoxide mutagenic derivative form of the substrate. The phase II metabolizing enzymes i.e. GSTs involve in catalysis of nucleophilic attack of Glutathione on substrates that are electrophilic thereby leaving them less reactive [24]. The conjugate of the substrate and glutathione is then pumped by a GS-X pump out of the cell for excretion [20].

Fig.4: Phase II detoxification system involving GSTs [19].

Diol epoxides (DEs) are the ultimate reactive species of polycyclic aromatic hydrocarbons (PAHs). Benzo[a]Pyrene is a PAH and the process of its metabolism in the human body involves the following steps. Firstly B[a]P is converted to an epoxide called B[a]P-7,8-epoxide in a reaction catalyzed by CYP1A1 of the P450 family. Secondly this epoxide is hydrolyzed by an enzyme epoxide hydrolase (EH) to form a dihydrodiol called B[a]P-7,8-dihydrodiol. Finally a second epoxidation results in the formation of B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE). BPDE thus formed is very mutagenic and forms DNA adduct at N2 position of Guanine hence causing mutations [54, 56].

Fig.5: Chemical detoxification mechanism in the cell [55].

The presence of GSTM1 positive genotype results in the expression of GSTM1 isoenzyme which initiates the conjugation of the electrophile with glutathione. This constitutes Phase II of metabolic detoxification. Individuals with null genotype are therefore more prone to mutagenesis by carcinogens [56].

Liver:

The class µ Glutathione S-transferase isoenzyme in the liver is expressed in about 50% of the adults. Therefore individuals who have a GSTM1 homozygous null genotype are deprived of glutathione transferase that helps in detoxification [13, 23]. The GSTM1 isoenzyme is involved in the detoxification by conjugating the extraneous chemicals with glutathione. Cysteine, glycine and glutamic acid together form the tripeptide glutathione. Water soluble mercaptates are produced as a result of conjugation reaction of the compounds with glutathione. The conjugated product is then expelled by means of kidneys [7].

LUNG

Plasma

RX

RX + GSH

HX + RSG

KIDNEY

Renal - Hepatic circulation

Fig.6: Conjugation of glutathione with electrophilic compounds in the liver

RX  Parent compound

GSH Glutathione

HX Leaving group

RSG Conjugate

Reference: [4, 7, 8]

The electrophiles or active metabolites are delivered to the liver via the blood plasma. The compound as shown in Fig.6 is conjugated with glutathione to form a less active and water soluble mercaptate which is further excreted via the kidney [4, 7, 8]. If the GSTM1 isoenzyme is not expressed then no detoxification occurs and this poses a risk of formation of DNA adducts by the mutagenic compound causing undesired mutations [14]. 4-aminobiphenyl is an important hepatic carcinogen that comes from cigarette smoke [15].

Leukemia:

Acute myeloid leukemia (AML) results from uncontrolled division of hematopoietic progenitor cell line. The stem cells differentiate into immature cells called blasts which accumulate in the bone marrow [29]. Studies report that GSTM1 polymorphism poses a potential risk in developing AML [17, 25]. Glutathione transferases metabolize several carcinogens preventing damage to DNA of hematopoietic stem cells. Individuals having a GSTM1 null genotype, lack the enzyme expression resulting in lack of ability to metabolize mutagenic carcinogens [25, 26]. Population with Null genotype hence is prone to mutations in tumor suppressor genes and important oncogenes [25]. The frequency of occurrence of GSTM1 null genotype varies based on various ethnic groups such as Caucasian whites (50%), and other groups (20-48.9%) respectively. Individuals with both GSTM1 and GSTT1 null genotype are at elevated risk of carcinogenesis [27]. DNA adducts formed by BPDE were found in blood samples of individuals having GSTM1 null genotype but no adducts were detected in individuals who had active GSTM1 [53].

Myeloma:

Studies confirm that there is no association between smoking and occurrence of multiple myeloma [48-52].

Esophagus:

A study by Wang et.al in 2002 [30] showed that individuals having GSTM1 null genotype are at a risk of esophageal cancer. Incidence of esophageal cancer varies from one ethnic group to another. GSTM1 null polymorphism increases incidence of chromosome aberrations due to exposure to nitrosamines from tobacco [31]. The gene deletion results in inability to detoxify activated metabolites and hence leading to carcinogenesis [32, 33]. GSTM1 isoenzyme is primarily involved in metabolic detoxification of Benzo(a)Pyrene and polyaromatic hydrocarbons [34].

Stomach:

GSTM1 null genotype was found to be associated with elevated risk of gastric cancer when compared to GSTM1 non-null genotype in Chinese population [35, 43]. This genotype occurs due to the inherited deletion of maternal and paternal alleles. As a result the ability to detoxify xenobiotics becomes less hence increasing risk of mutations. Risk of occurrence of Gastric cancer was more in individuals who had null genotype of both GSTM1 and GSTT1 [36].

Oral Cavity:

GSTM1 enzyme is primarily involved in detoxification of PAH and B(a)P. But no detoxification occurs when there is null genotype of GSTM1 since the enzyme is not expressed. This hence allows DNA adducts formation by carcinogens. The null genotype occurs in 20-50% of different ethnic groups. Japanese smoking population having null genotype, showed higher risk of Oral carcinoma. Even German population having null genotype showed susceptibility to cancer [37]. A study in Indian population showed that the risk of cancer in cigarette smokers having GSTM1 null genotype was 6 times more when compared to people having GSTM1 positive genotype [38].

Pharynx:

A meta-analysis on risk of nasopharyngeal carcinoma and GSTM1 polymorphism showed that GSTM1 null genotype increased risk of cancer [41].

Fig.7: No Detoxification leading to DNA damage [44]

Larynx:

Major heavy smokers suffering from laryngeal cancer were found to have GSTM1 null deletion polymorphism [39]. Deficiency of GSTM1 showed a rise in risk of laryngeal cancer in population of turkey [40].

Lung:

GSTM1 null genotype is associated with elevated risk of lung cancer [27, 28]. Population that carried homozygous deletion genotype of GSTM1 showed increased PAH DNA adducts. In the case of small lung cell carcinoma, there was an increase in p53 and K-ras mutations due to the presence of GSTM1 null and CYP1A1 genotypes [21]. The level of GSTM1 expression is generally low in lung compared to liver [28]. Benzo[a]Pyrene is a carcinogen in cigarette smoke which is metabolized to Benzo(a)pyrene-7,8-diol-9,10-epoxide (BPDE) which forms an adduct with DNA at N2 position of Guanine which is responsible for initiation of lung cancer [54].

Ovary:

Studies showed no evidence that GSTM1 genotypes had any influence on risk of ovarian cancer [45-47].

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