GSTP1 variants have been identified: P1^ A (104I, 113A), P1^ B (104V, 113A),
P1^ C (104V, 113V), and P1^ D (104I, 113V) (Table 3.13). The GSTP1^ 2 and
GSTP1^ 3 alleles produce variant enzymes that have a catalytic efficiency (kcat/
Km) that is three to four times lower than the most common GSTP1^ A allele.
The A313G polymorphism in GSTP1 results in Ile104Val conversion and is
relatively common (allele frequency = 0.26) (Table 3.14). The GSTP1^ 3 allele
is rare. Ile104 is in the hydrophobic substrate binding pocket of GSTP1-1.
3.3.8.3 GSTP1 Polymorphism and Cancer Cancer treatment regimens often
include alkylating agents such as busulfan, thiotepa, chlorambucil, and
melphalan. These drugs undergo glutathione conjugation that inactivates
these alkylating drugs. The major enzyme involved in this inactivation is the
GSTalpha and GSTpi class enzymes. The glutathione conjugates are removed
from tumor cells by transport proteins. Some tumors have increased expression
of these GSTs, a possible resistance mechanism. The glutathione conjugates
can also result in product inhibition of the GSTs and failure to remove the
GSTs by down regulation of the transporter expression may also play a role in
drug resistance in tumor cells. Several epidemiological studies have reported
associations of higher rates of testicular, oral pharyngeal, and bladder cancer
with these variant alleles, but not with breast, colon, or lung cancers. A recent
meta-analysis for prostate cancer has been completed examining the effects of
GST mu, pi, and theta polymorphisms (Ntais et al., 2005). Overall, no
significant random effects odd ratio (1.05 overall) were observed in these
studies, although individual studies have reported higher risks. The authors
concluded that the GST polymorphism were unlikely to be major risk factors
for prostate cancer (Table 3.15).
TABLE 3.13 Frequency of GSTP1 Polymorphisms in German control and cancer
patients (Risch et al., 2001).
Gene
Percentage in German
Caucasians
(controls) (%)Lung
cancer (%)Adenocarcinoma
(%)GSTP1^ 1/^ 1 (AA313) 47.3 (n = 167) 45.4 (n = 176) 46.4 (n = 70)
GSTP1^ 1/^ 2 (GA313) 42.8 (n = 151) 44.9 (n = 174) 45.7 (n = 69)
GSTP1^2 /^ 2 (GG313) 9.9 (n = 35) 9.8 (n = 38) 7.9 (n = 12)
TABLE 3.14 Frequency in GSTP1 allele frequencies in control groups
of Caucasians (Goto et al., 2002).
Gene Heterozygous Homozygous Allele frequency
GSTP1^1 0.493 0.438 0.685
GSTP1^2 0.442 0.413 0.262
GSTP1^3 0.126 0.0057 0.0687
1138 Controls tested for^ 1 and^ 2. 878 Controls tested for^ 3.
80 CONJUGATIVE METABOLISM OF DRUGS