GSTT1 plays a role in detoxification of carcinogens found in tobacco smoke and
pesticides, epoxybutanes and ethylene oxide. As opposed to the role of GSTM1,
GSTT1 has both detoxification and activation roles as seen in case of activation of
dihalomethanes to dichloromethane, which has been shown to cause liver and lung
tumors in mice. GSTT1 is different from other members of GST family as it is
expressed not only in the adult liver but also in human erythrocytes and thus has a
wider role in detoxification of carcinogens in the body (Landi 2000). The GSTT
subfamily is made up of two genes, GSTT1 and GSTT2.These are located at 22q11.2
and separated by about 50 kb having five exons each with identical intron/exon
boundaries. However, these share only 55% amino acid identity. There is no role of
GSTT2 in deletion of GSTT1 (Coggan et al. 1998). GSTT1 has two flanking 18 kb
regions named as HA3 and HA5 with >90% homology and having identical 403-bp
repeats, which function as deletion/junction regions of the GSTT1 null allele
(Sprenger et al. 2000). GSTT1 deletion results from a homologous recombination
event involving the left and right repeats causing a 54-kb deletion containing the
entire GSTT1 gene. Ethnic variations have been reported regarding the distribution
of null allele of GSTT1. Studies of GSTT1 null genotype demonstrate that 20% of
Caucasians, 47–64% of Asians, 15–31% of Europeans and 22–29% of African
Americans have deletion genotype of GSTT1. Asian populations have greater
prevalence of GSTT1 compared to the Europeans as shown by studies which report
21% of Italians and 28% of Slovakians have deletion while 58% of Chinese, 38% of
Malaysians (Lee et al. 1995), 42% and 46% Koreans have GSTT1 deletion
genotype.
GSTP1 is involved in the metabolism and detoxification of many carcinogenic
xenobiotics such as diol epoxides of polycyclic aromatic hydrocarbons (PAHs).
GSTP1 has been the focus of several studies because of its over-expression in
pre-neoplastic and tumor tissues which makes it useful as an early tumor marker,
and is also responsible for drug resistance of many cancers. GSTP1 gene is located at
11q13 and is 2.8 kb long with seven exons (Morrow et al. 1989). The open reading
frame starts at the 3
0 end of the first exon and is 630 bp long, encoding a protein of
209 amino acids. GSTP1 has two common non-synonymous SNPs that result in
Ile105Val and Ala114Val alterations in encoded amino acid sequence and are
associated with variations in cancer risk and treatment response (McIlwain et al.
2006). The effect of Val105 substitution is due to steric restriction of the H-site due
to shifts in the side chains of several amino acids which leads to less accommodation
of less bulky substrates than the Ile105 allozyme (Johansson et al. 1998). Moreover,
codon 105 variant allozyme has different thermal stability compared to the wild type
(Johansson et al. 1998). These are the probable reasons for the use of GSTP1 as an
early tumor marker and in pharmacogenetics. As seen with GSTM1 and GSTT1,
ethnic variations have also been reported in the distribution of variant genotypes of
GSTP1. In Africa, the frequency of GSTP1 Val105 variant has been reported to be
14% among South Africa, 16%, 12%, and 21% among Tanzanians, South African
Venda, and Zimbabweans, respectively (Dandara et al. 2002) and 53% (The
Gambia) (Wild et al. 2000). Caucasians have an allele frequency of 28–38%,
while Asians have 16–26%. Another polymorphism of GSTP1, A114V, is less
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M. Ruwali and R. Shukla
pesticides, epoxybutanes and ethylene oxide. As opposed to the role of GSTM1,
GSTT1 has both detoxification and activation roles as seen in case of activation of
dihalomethanes to dichloromethane, which has been shown to cause liver and lung
tumors in mice. GSTT1 is different from other members of GST family as it is
expressed not only in the adult liver but also in human erythrocytes and thus has a
wider role in detoxification of carcinogens in the body (Landi 2000). The GSTT
subfamily is made up of two genes, GSTT1 and GSTT2.These are located at 22q11.2
and separated by about 50 kb having five exons each with identical intron/exon
boundaries. However, these share only 55% amino acid identity. There is no role of
GSTT2 in deletion of GSTT1 (Coggan et al. 1998). GSTT1 has two flanking 18 kb
regions named as HA3 and HA5 with >90% homology and having identical 403-bp
repeats, which function as deletion/junction regions of the GSTT1 null allele
(Sprenger et al. 2000). GSTT1 deletion results from a homologous recombination
event involving the left and right repeats causing a 54-kb deletion containing the
entire GSTT1 gene. Ethnic variations have been reported regarding the distribution
of null allele of GSTT1. Studies of GSTT1 null genotype demonstrate that 20% of
Caucasians, 47–64% of Asians, 15–31% of Europeans and 22–29% of African
Americans have deletion genotype of GSTT1. Asian populations have greater
prevalence of GSTT1 compared to the Europeans as shown by studies which report
21% of Italians and 28% of Slovakians have deletion while 58% of Chinese, 38% of
Malaysians (Lee et al. 1995), 42% and 46% Koreans have GSTT1 deletion
genotype.
GSTP1 is involved in the metabolism and detoxification of many carcinogenic
xenobiotics such as diol epoxides of polycyclic aromatic hydrocarbons (PAHs).
GSTP1 has been the focus of several studies because of its over-expression in
pre-neoplastic and tumor tissues which makes it useful as an early tumor marker,
and is also responsible for drug resistance of many cancers. GSTP1 gene is located at
11q13 and is 2.8 kb long with seven exons (Morrow et al. 1989). The open reading
frame starts at the 3
0 end of the first exon and is 630 bp long, encoding a protein of
209 amino acids. GSTP1 has two common non-synonymous SNPs that result in
Ile105Val and Ala114Val alterations in encoded amino acid sequence and are
associated with variations in cancer risk and treatment response (McIlwain et al.
2006). The effect of Val105 substitution is due to steric restriction of the H-site due
to shifts in the side chains of several amino acids which leads to less accommodation
of less bulky substrates than the Ile105 allozyme (Johansson et al. 1998). Moreover,
codon 105 variant allozyme has different thermal stability compared to the wild type
(Johansson et al. 1998). These are the probable reasons for the use of GSTP1 as an
early tumor marker and in pharmacogenetics. As seen with GSTM1 and GSTT1,
ethnic variations have also been reported in the distribution of variant genotypes of
GSTP1. In Africa, the frequency of GSTP1 Val105 variant has been reported to be
14% among South Africa, 16%, 12%, and 21% among Tanzanians, South African
Venda, and Zimbabweans, respectively (Dandara et al. 2002) and 53% (The
Gambia) (Wild et al. 2000). Caucasians have an allele frequency of 28–38%,
while Asians have 16–26%. Another polymorphism of GSTP1, A114V, is less
222
M. Ruwali and R. Shukla