acid changes T122S (conservative) and E210A (at start of external helix).
Neither residue was in the active site. When expressed inE. coli, the kinetic
properties of the GSTA2-2 enzyme were not affected.
Coles et al. found variants in the promoter region of the human GSTA1
gene with four SNPs: The combination of631T or G,567T,69C,52G
was designated as hGSTA1^ A and 631G, 567G, 69T, 52A was
designated as hGSTA1^ B (Coles et al., 2001). Genotyping has been done for
the C–69T mutation and this relatively common in Caucasian, Asian, and
African populations (Table 3.10). Decreased expression was observed in a bank
of 55 liver samples that were heterozygous or homozygous for the^ B variant.
However, Bredschneider could find no relationship between haplotypes in a
separate liver bank (Bredschreider et al., 2002). They reported several other
polymorphisms in the GSTA1 gene. Busulfan, a chemotherapeutic agent, is an
index substrate for the enzyme. Conjugation of busulfan varied seven–eight
fold in 48 human liver samples. Expression of GSTA1-1 as determined by
Western blotting also was variable (25–205 pmole/mg cytosolic protein). Eight
SNPs were identified: a silent mutation (A365G) in exon 5 (Tetlow et al., 2001)
TABLE 3.8 GSTA1 and GSTA2 polymorphisms identified by BLAST and EST
analysis.
GST Sequence change Amino acid change Effect
GSTA1 115G>T Nonsense
GSTA1 159G>T Q35H
GSTA1 365G>A Silent None
GSTA1 598G>C Q199H
GSTA1 669A>C Stop codon to Tyr
GSTA2 322C>T L108F BLAST and EST only
GSTA2 335C>G T112S No effect on kinetics
GSTA2 389A>T N130I BLAST and EST only
GSTA2 517A>G S173G BLAST and EST only
GSTA2 588G>T K196N
GSTA2 629C>A E210A No effect on kinetics
TABLE 3.9 Frequencies of GSTA1 polymorphisms in Caucasians, Africans,
and Chinese populations.
Polymorphism
Australian
Caucasians
(n= 200)African
(Bantu and Creole)
(n= 99)Chinese
(n= 96)GSTA1 (K135K) 365G = 0.42 365G = 0.23 365G = 0.12
365A = 0.58 365A = 0.77 365A = 0.88
GSTA2 (T122S) S = 0.995 S = 0.995 S = 1
T = 0.005 T = 0.005 T = 0
GSTA2 (E210A) 629A = 0.84 629A = 0.606 629A = 0.812
629C = 0.16 629C = 0.394 629C = 0.188
76 CONJUGATIVE METABOLISM OF DRUGS