and are therefore important for both detoxification and maintaining cellular genomic
integrity.
On the basis of their degree of sequence identity, GSTs have been assigned to
eight families designated as Alpha (α), Mu (μ), Pi (π), Sigma (σ), Theta (θ), Zeta (ζ),
Omega (ω), and Kappa (κ). The different isoforms such as GSTM1, GSTM3,
GSTP1, and GSTT1have been shown to exhibit genetic polymorphisms. GSTM1,
GSTM3, and GSTP1are involved in the detoxification of the PAH diol epoxides
while GSTT1 detoxifies tobacco smoke components such as monohalomethanes and
reactive epoxide metabolites of butadiene. GSTM1 is a member of GSTM family of
enzymes and is involved in the detoxification of polycyclic aromatic hydrocarbons,
ethylene oxide, epoxides, and styrene (Takahiko et al. 2008). Both the lack of this
enzyme and overexpression can have consequences, as deficiency of this enzyme
increases the cancer risk due to decreased elimination of carcinogenic compounds
(Rebbeck 1997), while overexpression may result in chemotherapeutic resistance.
Some factors, such as genetic variations, may alter gene expression or enzyme
activity of GSTM1 and have an important bearing on cellular protection from
environmental and oxidative stress and response to drugs. GSTM1 gene has
8 exons flanked by two almost identical 4.2-kb regions and GSTM1*0 deletion
polymorphism is caused by a homologous recombination process involving both
repeats (Xu et al. 1998). Studies focussing on genetic polymorphisms of GSTM1
have compared the homozygous deletion genotype with genotypes having one
functional allele. Homozygous gene deletions exhibit variable frequencies in different ethnic groups. GSTM1 has two other alleles designated as GSTM1A and
GSTM1B which differ by a C > G substitution at base position 534 resulting in
the substitution of Asn > Lys at amino acid 172 (Seidegard et al. 1998) though this
results in no functional difference between the two alleles. GSTM1A and GSTM1B
are, therefore, categorized together as non-null conjugator phenotypes. Several
studies have reported an association between GSTM1*0 (homozygous deletion)
and increased risk of cancers and with better treatment outcomes.
The rates of prevalence of null genotypes of GSTM1 are high across several
ethnic groups with a meta-analysis of 30 studies (Garte et al. 2001) involving over
10,000 individuals reporting a frequency of 53% for the Caucasians and a similar
frequency was seen in Asians but lower in African Americans (16–36%). In the
USA, different ethnic groups exhibit differences in frequencies of GSTM1 such as
from 23% to 41% for persons of African descent, from 32% to 53% for persons of
Asian descent, from 40% to 53% for those of Hispanic descent, and from 35% to
62% for those of European descent. For South American populations, studies have
reported frequencies of 21% for Chileans (Quinones et al. 1999), 55% for Caucasian
Brazilians, 33% for Black Brazilians, and 20% for Amazonian Brazilians. European
populations also exhibit variations in deletion frequency with 46% for French, 53%
for Italians, 44% for Hungarians and 50% for the Slovaks. Some groups such as
Pacific Islanders and Malaysians have a very high GSTM1 deletion frequency of
62–100%. Similarly, other Asian populations, such as the Japanese and Chinese,
have frequencies ranging from 48% to 50% and 35% to 63%, respectively (Rebbeck
1997).
10 Interactions of Environmental Risk Factors and Genetic Variations: Association. . .
221
integrity.
On the basis of their degree of sequence identity, GSTs have been assigned to
eight families designated as Alpha (α), Mu (μ), Pi (π), Sigma (σ), Theta (θ), Zeta (ζ),
Omega (ω), and Kappa (κ). The different isoforms such as GSTM1, GSTM3,
GSTP1, and GSTT1have been shown to exhibit genetic polymorphisms. GSTM1,
GSTM3, and GSTP1are involved in the detoxification of the PAH diol epoxides
while GSTT1 detoxifies tobacco smoke components such as monohalomethanes and
reactive epoxide metabolites of butadiene. GSTM1 is a member of GSTM family of
enzymes and is involved in the detoxification of polycyclic aromatic hydrocarbons,
ethylene oxide, epoxides, and styrene (Takahiko et al. 2008). Both the lack of this
enzyme and overexpression can have consequences, as deficiency of this enzyme
increases the cancer risk due to decreased elimination of carcinogenic compounds
(Rebbeck 1997), while overexpression may result in chemotherapeutic resistance.
Some factors, such as genetic variations, may alter gene expression or enzyme
activity of GSTM1 and have an important bearing on cellular protection from
environmental and oxidative stress and response to drugs. GSTM1 gene has
8 exons flanked by two almost identical 4.2-kb regions and GSTM1*0 deletion
polymorphism is caused by a homologous recombination process involving both
repeats (Xu et al. 1998). Studies focussing on genetic polymorphisms of GSTM1
have compared the homozygous deletion genotype with genotypes having one
functional allele. Homozygous gene deletions exhibit variable frequencies in different ethnic groups. GSTM1 has two other alleles designated as GSTM1A and
GSTM1B which differ by a C > G substitution at base position 534 resulting in
the substitution of Asn > Lys at amino acid 172 (Seidegard et al. 1998) though this
results in no functional difference between the two alleles. GSTM1A and GSTM1B
are, therefore, categorized together as non-null conjugator phenotypes. Several
studies have reported an association between GSTM1*0 (homozygous deletion)
and increased risk of cancers and with better treatment outcomes.
The rates of prevalence of null genotypes of GSTM1 are high across several
ethnic groups with a meta-analysis of 30 studies (Garte et al. 2001) involving over
10,000 individuals reporting a frequency of 53% for the Caucasians and a similar
frequency was seen in Asians but lower in African Americans (16–36%). In the
USA, different ethnic groups exhibit differences in frequencies of GSTM1 such as
from 23% to 41% for persons of African descent, from 32% to 53% for persons of
Asian descent, from 40% to 53% for those of Hispanic descent, and from 35% to
62% for those of European descent. For South American populations, studies have
reported frequencies of 21% for Chileans (Quinones et al. 1999), 55% for Caucasian
Brazilians, 33% for Black Brazilians, and 20% for Amazonian Brazilians. European
populations also exhibit variations in deletion frequency with 46% for French, 53%
for Italians, 44% for Hungarians and 50% for the Slovaks. Some groups such as
Pacific Islanders and Malaysians have a very high GSTM1 deletion frequency of
62–100%. Similarly, other Asian populations, such as the Japanese and Chinese,
have frequencies ranging from 48% to 50% and 35% to 63%, respectively (Rebbeck
1997).
10 Interactions of Environmental Risk Factors and Genetic Variations: Association. . .
221