CYP2A6 gene (Oscarson 2001). The CYP2A6 gene is 6 kb in size, has 9 exons, and
is located within a 350-kilobase pair gene cluster made up of CYP2A7, CYP2A13,
two CYP2A7 pseudogenes, and genes in CYP2B and CYP2F subfamilies (Hoffman
et al. 1995). CYP2A6 exhibits several genetic polymorphisms such as wild type
(CYP2A6*1A), gene conversion with CYP2A7 in the 3
0 -untranslated region
(CYP2A6*1B), gene conversions with CYP2A7 in exons 3, 6, and
8 (CYP2A6*3), L160H (CYP2A6*2), G479V (CYP2A6*5), R128Q
(CYP2A6*6), I471T (CYP2A6*7), R485L (CYP2A6*8), and S224P
(CYP2A6*11) (Daigo et al. 2002). Other functionally important alleles include
CYP2A6*9 which has a point mutation in the TATA box (T-48G), CYP2A6*10
(two simultaneous amino acid substitutions of CYP2A6*7 and CYP2A6*8),
CYP2A6*4 (deletion of the whole CYP2A6 gene), and CYP2A6*1X2 (duplication
of the CYP2A6 gene). Asian populations (Chinese, Japanese, and Korean) have
higher prevalence of CYP2A6 variant alleles resulting in reduced enzyme activity as
opposed to the Caucasian and African North American populations (Schoedel et al.
2004). Asian populations have prevalence of whole-gene deletion alleles
(CYP2A6*4B and CYP2A6*4C), while European population have higher frequency
of CYP2A6*2 and CYP2A6*3.
CYP2E1 metabolizes ethanol, low-molecular weight solvents, and tobacco specific nitrosamines. It is present on the tenth chromosome with 9 exons, 8 introns and
has a characteristic TATA box (Guengerich et al. 1991). CYP2E1gene has several
polymorphisms majority of which are present in the introns while others are present
in 5
0 -regulatory, intron, and transcribed regions. The polymorphisms studied with
restriction enzymes include PstI (G to C substitution at -1293 bp in the 5’noncoding
region of the CYP2E1gene) and RsaI (C to T substitution at À1053 in 5’noncoding
region of the CYP2E1) which are in linkage disequilibrium and together called as
CYP2E1*5B, with c1 and c2 alleles (Watanabe et al. 1990). c2 allele results in about
ten-fold higher gene transcription, protein level, and enzyme activity compared to
the c1 allele. Another polymorphism studied using restriction enzyme XbaI is
CYP2E1*1C having 43–60 bp six repeats and CYP2E1*1D with eight repeats.
The intron region of CYP2E1also has several polymorphic sites such as
DraI which constitutes a T to A substitution at 7668 bp in intron 6 that delete
DraI restriction enzyme cleavage site and is represented as CYP2E1*6 allele. DraI
polymorphism has two homozygous genotypes named as CC and DD and one
heterozygous genotype, CD (Stephens et al. 1994). Conflicting reports are present
regarding the effect of CYP2E1*6 on expression and activity with Persson et al.
(1993) observing no effect while Uematsu et al. (1991) reported altered CYP2E1
catalytic activity with CYP2E1*6 allele but no effect on gene transcription. Another
polymorphism present in intron 6 region of CYP2E1gene is the MspI polymorphism
which leads to the A-G replacement at 6827 bp causing deletion of MspI restriction
enzyme cleavage site. Little information is available about this polymorphism and it
does not affect the expression or enzyme activity. There are several polymorphism of
CYP2E1 which are present on coding region and lead to amino acid replacements
(Danko and Chaschin 2005). The distribution of CYP2E1 genotypes exhibit ethnic
variations with most of the polymorphisms of CYP2E1reported in Caucasians as
10 Interactions of Environmental Risk Factors and Genetic Variations: Association. . .
219
is located within a 350-kilobase pair gene cluster made up of CYP2A7, CYP2A13,
two CYP2A7 pseudogenes, and genes in CYP2B and CYP2F subfamilies (Hoffman
et al. 1995). CYP2A6 exhibits several genetic polymorphisms such as wild type
(CYP2A6*1A), gene conversion with CYP2A7 in the 3
0 -untranslated region
(CYP2A6*1B), gene conversions with CYP2A7 in exons 3, 6, and
8 (CYP2A6*3), L160H (CYP2A6*2), G479V (CYP2A6*5), R128Q
(CYP2A6*6), I471T (CYP2A6*7), R485L (CYP2A6*8), and S224P
(CYP2A6*11) (Daigo et al. 2002). Other functionally important alleles include
CYP2A6*9 which has a point mutation in the TATA box (T-48G), CYP2A6*10
(two simultaneous amino acid substitutions of CYP2A6*7 and CYP2A6*8),
CYP2A6*4 (deletion of the whole CYP2A6 gene), and CYP2A6*1X2 (duplication
of the CYP2A6 gene). Asian populations (Chinese, Japanese, and Korean) have
higher prevalence of CYP2A6 variant alleles resulting in reduced enzyme activity as
opposed to the Caucasian and African North American populations (Schoedel et al.
2004). Asian populations have prevalence of whole-gene deletion alleles
(CYP2A6*4B and CYP2A6*4C), while European population have higher frequency
of CYP2A6*2 and CYP2A6*3.
CYP2E1 metabolizes ethanol, low-molecular weight solvents, and tobacco specific nitrosamines. It is present on the tenth chromosome with 9 exons, 8 introns and
has a characteristic TATA box (Guengerich et al. 1991). CYP2E1gene has several
polymorphisms majority of which are present in the introns while others are present
in 5
0 -regulatory, intron, and transcribed regions. The polymorphisms studied with
restriction enzymes include PstI (G to C substitution at -1293 bp in the 5’noncoding
region of the CYP2E1gene) and RsaI (C to T substitution at À1053 in 5’noncoding
region of the CYP2E1) which are in linkage disequilibrium and together called as
CYP2E1*5B, with c1 and c2 alleles (Watanabe et al. 1990). c2 allele results in about
ten-fold higher gene transcription, protein level, and enzyme activity compared to
the c1 allele. Another polymorphism studied using restriction enzyme XbaI is
CYP2E1*1C having 43–60 bp six repeats and CYP2E1*1D with eight repeats.
The intron region of CYP2E1also has several polymorphic sites such as
DraI which constitutes a T to A substitution at 7668 bp in intron 6 that delete
DraI restriction enzyme cleavage site and is represented as CYP2E1*6 allele. DraI
polymorphism has two homozygous genotypes named as CC and DD and one
heterozygous genotype, CD (Stephens et al. 1994). Conflicting reports are present
regarding the effect of CYP2E1*6 on expression and activity with Persson et al.
(1993) observing no effect while Uematsu et al. (1991) reported altered CYP2E1
catalytic activity with CYP2E1*6 allele but no effect on gene transcription. Another
polymorphism present in intron 6 region of CYP2E1gene is the MspI polymorphism
which leads to the A-G replacement at 6827 bp causing deletion of MspI restriction
enzyme cleavage site. Little information is available about this polymorphism and it
does not affect the expression or enzyme activity. There are several polymorphism of
CYP2E1 which are present on coding region and lead to amino acid replacements
(Danko and Chaschin 2005). The distribution of CYP2E1 genotypes exhibit ethnic
variations with most of the polymorphisms of CYP2E1reported in Caucasians as
10 Interactions of Environmental Risk Factors and Genetic Variations: Association. . .
219