species (hydrogen peroxide, OH radicals). There is an antioxidant response
element (ARE) in theGSTA1,GSTA3,GSTM1, andGSTP1promoter regions.
The transcription factor Nrf2 binds to the ARE. Normally, Nrf2 is confined to
the cytoplasm and is bound to the actin-binding protein Keap1. Electrophiles
cause Nrf2 to dissociate from Keap1 (by reacting with thiols or activating
kinases) allowing Nrf2 to go to the nucleus and form heterodimers with small
Maf protein. The heterodimeric complex then binds to AREs (Hototashi and
Yamamoho, 2004). Other ARE containing proteins include UGT1A1, NQO1
(quinone reductase),g-glutamylcysteine synthase (necessary for GSH produc-
tion), cysteine-glutamate exchange transporter (responsible for cysteine
uptake), heme oxygenase-1, thioredoxin, and MRP1. Nrf2-knockout mice
are more sensitive to acetaminophen and butylated hydroxytoluene (BHT)
toxicity and have increased cancer rates when exposed to diesel exhaust,
aflatoxin, or benzo(a)pyrene (Itoh et al., 2004). Several chemopreventative
agents also upregulate GSTs via Nrf2 release such as sulforophane (in
broccoli), oltipraz, and isothiocyanates such as 3-methylsulfinylpropyl
isothiocyanate (in broccoli) or glucosinolates present in the seeds of cruciferous
vegetables (McWalter et al., 2004).
3.3.6 GST Alpha Class
3.3.6.1 GSTA Substrates GSTA1-1 –D^5 -androstene-3,17-dione (isomerase),
D^5 -pregnane 3,20-dione, PGA 2 , PGJ 2 (R-isomer conjugate favored)Busulfan,
Bay region diol epoxides of PAHs (synorR>S), for example B(a)P-diol
epoxide, moderate chlorodinitrobenzene (CDNB), low 1,2-dichloro-4-nitro-
benzene (DCNB) activity, various nitrogen mustards, such as chlorambucil
and melphalan, busulfan, doxorubicin, vincristine, etoposide, mitoxantrone,N-
acetoxy-PhiP, fatty acid hydroperoxides.
GSTA2-2Cumene hydroperoxide, fatty acid hydroperoxides, dibenzo(a)-
pyrene diol epoxide, CDNB-moderate, DCNB-moderate, 7-chloro-4-
nitro-2-oxa-1,3-diazole, ethacrynic acid (low–moderate), PEITC,
sulforophane.
GSTA3-3D^5 -androstene-3,17-dione,D^5 -pregnene-3,20-dione, DBPDE.
GSTA4-44-hydroxynonenal (HNE), 4-hydroxydecenal, crotonyloxy-
methyl-2-cylohexenone (COMC-6), CDNBlow, ethacrynic acidlow.3.3.6.2 Polymorphisms in the Alpha Class GSTs Board and coworkers
identified several SNPs by analysis of an expressed sequence tag (EST)
database containing sequence from 300 human cDNA libraries (Tetlow et al.,
2001) Ten polymorphisms were identified in the coding region of the GSTA1
and GSTA2 genes, and six were verified by sequence analysis (Table 3.8). PCR/
RFLP analysis identified three variants in GSTA2 that were present in
Caucasians (Australian), Bantu and Creole Africans, and Chinese populations
(Table 3.9). One was a silent mutation (365G>A) and two encoded for amino
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