Glutathiones Transferases Play Important Role Detoxification Xenobiotics Biology Essay

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Glutathione S-transferases (GSTs) are expressed in many organisms. They are involved in catalysis of the conjugation of glutathione (GSH) with various electrophilic compounds. They also play an important role in detoxification of xenobiotics. In general GSTs have been found to be involved in the providing resistance to chemotherapeutic agents and in signaling pathway regulation that helps in control of cancer cell survival and cell death [1]. GSTs are grouped under phase II metabolizing enzymes superfamily. They also play an important role in detoxification of ROS and maintenance of the cellular redox state [10]. Although GSTs were early investigated because of their enzymatic activity involved in the conjugation of GSH to a wide range of electrophilic metabolites and effects on protecting tumor cells against toxic drugs and oxidative stress, they were then discovered as 'ligandins' owing to their abilities to interact covalently and non-covalently with various compounds that were not substrates for enzymatic activity, including steroids, thyroid hormones, bilirubin, prostaglandins and bile acid [10].

GSTP-1 & Cancer:

Chemotherapeutic agent resistant human tumor cell lines over express class pi GST (GSTP-1). Cancers such as ovarian, lung, kidney, colon and breast cancer usually involve high expression of GSTP-1 compared to surrounding tissues [1].

GSTP-1 has been shown to be involved in the inhibition of c-Jun N-terminal kinase (JNK) through direct protein-protein interaction. JNK is a mitogen-activated protein kinase that is involved in apoptosis, cell differentiation, inflammation and proliferation. Activated JNK phosphorylates c-Jun, a component of the Activator Protein-1 (AP-1) transcription factor. This activation causes induction of AP-1-dependent target genes that lead to cell proliferation or cell death [1].

GSTP1-1 has also been reported to associate with tumor necrosis factor receptor-associated factor2 (TRAF2) and inhibit TRAF2-induced activation of both JNK and p38-MAPK. GSTP1-1inhibited TRAF2-enhanced apoptosis signal-regulating kinase 1 (ASK1) auto-phosphorylation andTRAF2-ASK1-induced cell apoptosis [1].

Protein Structure:

Characteristics of GSTP-1:

Synonyms: FAEES3, GST3, DFN7, PI

Locus: 11q13.2 [12]

Chromosome: 11

Sequence length: 210 AA.

GSTP-1 has two domains namely GST N-terminal (Position: 2-81; Length: 80) and GST C-terminal (Position: 83-204; Length: 122)

Function: Conjugation of reduced glutathione to no. of endogenous and exogenous hydrophobic electrophiles [6, 9].

Function of GSTP-1:

GSTs have been found to be involved in the biosynthesis and metabolism of prostaglandins, steroids and leukotrienes. They play an important role in modulation of cell signaling and control of cell proliferation and apoptosis. They are also involved in the management of toxic products of lipid oxidation and S-glutathiolated proteins generated by oxidative stress [2].

GSTP-1 and JNK cascade:

GSTP-1 in cell signaling [2]

According to studies, under non-stressed conditions, GSTP1 monomer inhibits c-Jun N-Terminal kinase (JNK) through formation of a protein complex. JNK or stress activated kinase, belongs to the mitogen stress kinase family (MAPK), which also includes extracellular signal regulated kinase and p38-MAPK [14]. Occurrence of oxidative stress causes GSTP1 to dissociate from JNK and subsequent formation of inactive covalent dimers. Under these conditions, full JNK activity is restored by JNK leading to activation of c-Jun through phosphorylation at Ser-63 or Ser-73 residues and increased transcription of AP-1-responsive genes. This results in activation of signaling pathways for stress response, proliferation and apoptosis. Studies also suggest that reactive oxygen species (ROS)-generating agents activate GSTP1 transcription via the JNK/Jun cascade and form a subtle regulatory loop dependent on the duration and magnitude of stress kinase activity. Through transcriptionally active JNK substrates, including c-Jun, new synthesis of GSTP1 occurs, which is expected to resume JNK inhibition. Thus, GSTP1 influences signaling pathways for apoptosis by modulating JNK kinase activity [3].

GSTP-1 and TRAF2:

Tumor necrosis factor-α (TNF-α) is a cytokine that is widely involved in activation of transcription factors. Tumor necrosis factor receptor associated factor 2 (TRAF2) is a member of the TRAF family, which is a signal transducer for the TNF receptor family [10]. Stimulation of the receptor TNF-R1 leads to the recruitment of the adaptor TRAF2 and simultaneous activation of a phosphatase mechanism. The association of apoptosis signal-regulating kinase 1 (ASK1) with AIP1 is mediated by TRAF2. As a result ASK1 is released from its endogenous inhibitor 14-3-3 and simultaneous de-phosphorylation occurs (fig.). ASK1 now activates the c-Jun NH2- terminal kinase (JNK) via MKK4 or MKK6 dependent pathway. Activated JNK is involved in regulation of apoptosis. GSTP1 inhibits TNF- α induced TRAF2-ASK1-JNK cascade activation and cell apoptosis. GSTP1 competes with ASK1 for binding to the TRAF domain of TRAF2 [11]. Subjects with the combination of GSTM1 null and GSTP1 AG or GG genotypes are more susceptible to smoking-induced inflammation than those with the other genotype combinations [16].

Effect of Carcinogens on GSTP-1:

A no. of studies has shown the association between active smoking and lung cancer risk by genetic polymorphisms. Genes involved in Phase I and II metabolism are involved directly in the metabolisms of tobacco smoke carcinogens (BaP, PAH etc.). Glutathione S-transferases, a major group of enzymes, whose main classes are α, µ, π and θ, are directly involved in the detoxification step of metabolism (Phase II). The expression of these enzymes differs among organs. GST π has the highest expression in the lung and is one of the main detoxifiers of the activated form of benzopyrene, a major carcinogen of tobacco smoke. GST π is encoded by a polymorphic gene, GSTP1. The polymorphism in GSTP1 occurs as a result of a single base pair substitution, where adenine is replaced by guanine (A313G), leading to an amino acid substitution in which Isoleucine (I105) is replaced by Valine (V105). This substitution results in a lower enzymatic activity, and is associated with higher hydrophobic adduct levels in lung tissue and higher levels of PAH-DNA adducts in human lymphocytes [4].

Molecular Genetics

The work of Ali-Osman et al. (1997) involved isolation of cDNAs corresponding to 3 polymorphic GSTP1 alleles, GSTP1*A, GSTP1*B, and GSTP1*C as a result of A-to-G and C-to-T transitions at nucleotides 313 and 341, respectively. The transitions changed codon 105 from ATC (ile) in GSTP1*A to GTC (val) in GSTP1*B and GSTP1*C, and changed codon 114 from GCG (ala) to GTG (val) in GSTP1*C. Both amino acid changes are in the electrophile-binding active site of the GST-pi peptide [7].

GSTP-1 and lung Cancer:

According to a study the most common lung tumor is squamous cell carcinoma in the case of men and adenocarcinoma in women. GSTP1 mainly detoxifies the polycyclic aromatic hydrocarbons present in cigarette smoke [8]. It was determined in the study that GSTP1 exon5 (ile105val) polymorphism is associated with the increase in lung cancer risk by about 7.5 times higher in individuals who have homozygote allele G [5]. Exon 5 GSTP1 genetic polymorphism occurs in 3 existing genotypes: GSTP1*A/*A (Ile/Ile), GSTP1*A/*B (Ile/Val) and GSTP1*B/*B (Val/Val). Another well-known genetic polymorphism of GSTP1 is connected with Ala to Val change at codon 114 [13].

GSTP1 and cancer of Pharynx and Oral cavity:

A study supported the view that GSTP1 polymorphism is involved in modulating the susceptibility to cancers of oral cavity and pharynx. GSTP1 (AG or GG) genotype was found to pose a 2 fold increase in risk of cancer [14].