3.3.7.2 Substrates GSTM1-1Trans-stilbene oxide,DCNB-high, CDNB-mod-
erate, Aflatoxin B1-exo8,9-epoxide, androstene 3,17-dione, B(a)P-diol epoxide,
B(a)P-4,5-oxide, chrysene diol epoxide, cumene hydroperoxide, ethacrynic acid,p-
nitrophenyl acetate, PGA2, PGJ2, styrene 7,8-oxide,trans-4-phenyl-3-buten-2-one.
GSTM2-2Dopa o-quinones, PGH 2 to PGE2,DCNB-high, CDNB-high,
aminochrome, 2-cyano-1,3-dimethyl-1nitroso-guanidine.
GSTM3-3BCNU, PGH 2 to PGE 2 , CDNB-low, DCNB-low, cumene
hydroperoxide-low, ethacrynic acid-low.
GSTM4-4CDNB-low, DCNB-low, cumene hydroperoxide-low, ethacry-
nic acid-low.
GSTM5-5CDNB-moderate to low.3.3.7.3 Polymorphisms Approximately 50% of Caucasians and E. Asians
do not have a gene for GSTM1. This is termed the null allele (GSTM1 0 ). In
some Polynesian and Micronesian populations, the allele frequency is very high
(90%), whereas in Africans, the null allele occurs much less frequently (20–
25% homozygous for the null genotype) (Table 3.12).
3.3.7.4 Polymorphisms and Effects on Drug Metabolism or Drug Toxicity
Cisplatin is an important chemotherapeutic agent with dose-limiting side
effects of ototoxicity, nephrotoxicity, and peripheral neuropathies. Peters et al.
examined GST polymorphisms and cisplatin-induced ototoxicity (Peters et al.,
2000). A significant protective effect was observed for the GSTM3^ B allele
(GSTM3 AA). The frequency of this allele was 0.18 in a group with normal
hearing (n= 19) treated with cisplatin versus 0.025 in the group with early
hearing impairment (n= 20).
3.3.7.5 Role in Cancer Since glutathione conjugation is a primary means of
detoxifying electrophiles, its role in cancer has been extensively investigated.
TheGSTM1gene deletion deficiency (present in 50% of Caucasians) has been
associated with a moderate increased risk for lung and bladder cancer
(RR = 1.5–2.0). Many studies on other types of cancers show a minimal effect.
The relationship between GSTM1 variants, alone or in combination with
CYP1A1 (a bioactivating enzyme, expressed in epithelial tissues) and polycyclic
aromatic hydrocarbon DNA adducts is still controversial. More recent studies
have shown a clear dependence upon CYP1A1 genotype especially in GSTM1-
deficient smokers, despite their relatively low expression in the lung. Benzo(a)
pyrene 7,8-diol-9,10-epoxide (BPDE) adducts were 100 higher inGSTM1 0/0
smokers with a CYP1A1 high inducibility genotype compared to subjects with
active GSTM1 (Bartsch, 1996). Several other studies also indicate a strong
relationship with GSTM1 and DNA adducts (reviewed by Bartsch, 2000).
Linkage studies have failed to identify a role for GSTM3 in lung cancer,
adenocarcinomas, small cell lung carcinoma (Risch, 2001), or in astrocytomas.
A positive risk was identified in bladder cancer (OR = 2.31, CI 1.7–2.82) for
GSTM3 AA genotype and for the GSTM1 null genotype (OR = 3.54,
78 CONJUGATIVE METABOLISM OF DRUGS