conserved, while almost all CYPs involved in xenobiotic metabolism are functionally polymorphic (Ingelman-Sundberg 2004). CYP1 family, which consists of
CYP1A and CYP1B1, is involved in the metabolic activation of procarcinogens
and promutagens to reactive carcinogenic and mutagenic species while CYP2 family
which includes CYP2A, 2B, 2C, 2D, and 2E accounts for metabolism of majority of
drugs. CYP2E1 is also primarily involved in the metabolism of alcohol and other
low-molecular weight compounds and contributes to activation of many
procarcinogens and several drugs to highly reactive metabolites (Nakajima and
Aoyama 2000). Likewise, CYP2A6 has been specifically demonstrated to activate
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N
0 -nitrosonornicotine
(NNN) tobacco smoke procarcinogens via α-hydroxylation (Patten et al. 1997).
CYPs belonging to 2C and 2D family are the major drug metabolizing CYPs and
lead to poor or extensive metabolizer phenotype.
CYP1 family members include three genes, CYP1A1, CYP1A2, and CYP1B1.
CYP1A1 gene is located on the long arm of chromosome 15 (q22–24) and contains
seven exons of which the first is noncoding (Hildebrand et al. 1985). The CYP1A1
m1 polymorphism (CYP1A1*2A) consists of a T-C substitution in the 3
0 noncoding
region of the gene, m2 polymorphism (CYP1A1*2C) is due to an A to G substitution
at nucleotide 4889 in exon 7, m3 polymorphism (T5639C) is found only in African
Americans, and m4 polymorphism (CYP1A1*4) leads to a C to A substitution
(Cascorbi et al. 1996). While, both CYP1A1*2A and CYP1A1*2C have been
reported in Asians, the frequency of CYP1A1*2C is rare in the Caucasians (Hung
et al. 2003). CYP1A2 is also located on chromosome 15q22-q24 but shows different
substrate specificity from CYP1A1 with a preference for heterocyclic amines,
caffeine and a limited number of prescribed drugs including antipsychotics and
theophylline (Schmidt 1996). Functionally important polymorphisms in the
CYP1A2 are identified in upstream sequence and intron 1 and some of these may
affect CYP1A2 protein expression. CYP1A2*1C results from a single nucleotide
change from G to A at position À3858 in 5
0
flanking region (Nakajima et al. 1999).
The frequency of variant allele of CYP1A2*1C is estimated to be around 0.02–0.03
per cent in Caucasians and higher frequency is found in Japanese (0.10) and Chinese
population (0.11). The second variant allele is a C to A transversion (CYP1A2*1F)
in intron 1 at position 734 downstream of the first CYP1B1, located on chromosome
2, 2p21. Of the most common SNPs of CYP1B1 gene, four have been reported to
result in amino acid substitutions including Arg by Gly at codon 48 (CYP1B1*2),
Ala by Ser at codon 119 (CYP1B1*2), Leu by Val at codon 432 (CYP1B1*3), and
Asn by Ser at codon 453 (CYP1B1*4). A higher catalytic activity for Val432
variants than the Leu432 variants of the enzyme have been reported suggesting
that polymorphisms in the human CYP1B1 gene, especially those at codon 432, may
contribute to differential susceptibility towards PAH and tobacco-induced cancers
(Shimada et al. 1999).
CYP2 is the largest CYP family made up of 13 subfamilies which are involved in
drug metabolism in mammals. The genes which code for proteins are CYP2A
CYP2B, CYP2C, CYP2D, CYP2E, CYP2F, CYP2J, CYP2R, CYP2S, and
CYP2W while CYP2A7 is the pseudogene which produces a hybrid gene with the
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M. Ruwali and R. Shukla
CYP1A and CYP1B1, is involved in the metabolic activation of procarcinogens
and promutagens to reactive carcinogenic and mutagenic species while CYP2 family
which includes CYP2A, 2B, 2C, 2D, and 2E accounts for metabolism of majority of
drugs. CYP2E1 is also primarily involved in the metabolism of alcohol and other
low-molecular weight compounds and contributes to activation of many
procarcinogens and several drugs to highly reactive metabolites (Nakajima and
Aoyama 2000). Likewise, CYP2A6 has been specifically demonstrated to activate
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N
0 -nitrosonornicotine
(NNN) tobacco smoke procarcinogens via α-hydroxylation (Patten et al. 1997).
CYPs belonging to 2C and 2D family are the major drug metabolizing CYPs and
lead to poor or extensive metabolizer phenotype.
CYP1 family members include three genes, CYP1A1, CYP1A2, and CYP1B1.
CYP1A1 gene is located on the long arm of chromosome 15 (q22–24) and contains
seven exons of which the first is noncoding (Hildebrand et al. 1985). The CYP1A1
m1 polymorphism (CYP1A1*2A) consists of a T-C substitution in the 3
0 noncoding
region of the gene, m2 polymorphism (CYP1A1*2C) is due to an A to G substitution
at nucleotide 4889 in exon 7, m3 polymorphism (T5639C) is found only in African
Americans, and m4 polymorphism (CYP1A1*4) leads to a C to A substitution
(Cascorbi et al. 1996). While, both CYP1A1*2A and CYP1A1*2C have been
reported in Asians, the frequency of CYP1A1*2C is rare in the Caucasians (Hung
et al. 2003). CYP1A2 is also located on chromosome 15q22-q24 but shows different
substrate specificity from CYP1A1 with a preference for heterocyclic amines,
caffeine and a limited number of prescribed drugs including antipsychotics and
theophylline (Schmidt 1996). Functionally important polymorphisms in the
CYP1A2 are identified in upstream sequence and intron 1 and some of these may
affect CYP1A2 protein expression. CYP1A2*1C results from a single nucleotide
change from G to A at position À3858 in 5
0
flanking region (Nakajima et al. 1999).
The frequency of variant allele of CYP1A2*1C is estimated to be around 0.02–0.03
per cent in Caucasians and higher frequency is found in Japanese (0.10) and Chinese
population (0.11). The second variant allele is a C to A transversion (CYP1A2*1F)
in intron 1 at position 734 downstream of the first CYP1B1, located on chromosome
2, 2p21. Of the most common SNPs of CYP1B1 gene, four have been reported to
result in amino acid substitutions including Arg by Gly at codon 48 (CYP1B1*2),
Ala by Ser at codon 119 (CYP1B1*2), Leu by Val at codon 432 (CYP1B1*3), and
Asn by Ser at codon 453 (CYP1B1*4). A higher catalytic activity for Val432
variants than the Leu432 variants of the enzyme have been reported suggesting
that polymorphisms in the human CYP1B1 gene, especially those at codon 432, may
contribute to differential susceptibility towards PAH and tobacco-induced cancers
(Shimada et al. 1999).
CYP2 is the largest CYP family made up of 13 subfamilies which are involved in
drug metabolism in mammals. The genes which code for proteins are CYP2A
CYP2B, CYP2C, CYP2D, CYP2E, CYP2F, CYP2J, CYP2R, CYP2S, and
CYP2W while CYP2A7 is the pseudogene which produces a hybrid gene with the
218
M. Ruwali and R. Shukla