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Pharmacogenetics: CYP1A2 Genetic Polymorphisms

  • GENETIC POLYMORPHISMS OF CYTOCHROME P450 (CYP) 1A2
     Allele Population
    Single Nucleotide
    Polymorphism

    Location
    CYP1A2
    Activity

    Notes
     CYP1A2*1
    General Population Wild-type; 7.8kb
    15q24.1
    normal
    Contains 7 exons & 6
    introns that code for a
    515-residue protein with
    a MW of 58,294 Da
     CYP1A1*1B
    Chinese
    French caucasians 35%
    C5347T (N516N)
    Exon 7 unknown
    Impact not known
     CYP1A2*1C
    Japanese G-3860A
    Enchancer

    Associated with ↓
    inducibility of 1A2
     CYP1A2*1D
    Turkish 92%
    Japanese 42-44%
    Egyptians 40%
    T-2467delT Enhancer
    unknown
    Impact not known
     CYP1A2*1E
    Japanese 42%
    Caucasians 4.8%
    T-739G
    Intron 1
    unknown
    Impact not known
     CYP1A2*1F
    British whites 33%
    German whites 32%
    C-163A
    Intron 1

    Associated with ↑1A2
    production/activity
     CYP1A2*1J
    Saudi Arabains 5.9%
    Spaniards 1.3%
    -740G; -164A
    Intron 1
    unknown Impact currently
    unknown
     CYP1A2*1K
    Saudi Arabians 3.6%
    Spaniards 0.5%
    -730T; -740G;
    -164A
    Intron 1
    May disrupt transcription
    factor binding that leads
    to ↓transcription
     CYP1A2*2
    Chinese 0.32%
    C2866G (F21L)
    Exon 2
    unknown
    Impact not known
     CYP1A2*3
    French ≤ 0.5-1% T5347T (D348N)
    Exon 4

    ↓gene expression
     CYP1A2*4
    French ≤ 0.5-1%
    A2499T (I383F) Exon5
    ↓gene expression
     CYP1A2*5
    French ≤ 0.5-1%
    G3497A (C406Y) Exon 6
    unknown
    Impact not known
     CYP1A2*6
    French ≤ 0.5-1%
    G5090T (R431W)
    Exon 7

    ↓gene expression
     CYP1A2*7
    NR
    G3533A
    Intron 6

    Splicing defect in gene
     CYP1A2*8
    Japanese < 1%
    G5166A (R456H)
    Exon 7

    Impact in-vivo not known
     CYP1A2*9
    Japanese < 1%
    C248T (T38M)
    Exon 2
    unknown Impact not known
     CYP1A2*10
    Japanese < 1%
    G502C (E168Q)
    Exon 2
    unknown
    Impact not known
     CYP1A2*11
    Japanese < 1%
    C558A (F186L)
    Exon 2

    Impact in-vivo not known
     CYP1A2*12
    Japanese < 1%
    A634T (S212C)
    Exon 2
    unknown
    Impact in-vivo not known
     CYP1A2*13
    Japanese < 1%
    G1514A (G299S)
    Exon 3
    unknown
    Impact in-vivo not known
     CYP1A2*14
    Japanese < 1%
    C5112T (T438I)
    Exon 7
    normal
    Impact in-vivo not known
     CYP1A2*15
    Japanese < 1%
    C125G (P42R)
    Exon 2

    Impact in-vivo not known
     CYP1A2*16
    Japanese < 1%
    G2473A (R377Q)
    Exon 5

    Impact in-vivo not known


    The letters  before and after the numbers represent the single nucleotides that make up the DNA sequence and to code for an amino acid (A = adenine, C = cytosine, G = guanine, T = thymine).  Amino acids represented: (C = cysteine, D = aspartate, F = phenyalanine, G = glycine, H = histidine, K = lysine, L = leucine, M = methionine, N = asparagine, P = proline, Q = glutamine, R = arginine, S = serine, T = threonine, V = valine, W = tryptophan, Y = tyrosine).  NR = not reported.

    REFERENCES:

    1. Zhou SF, Wang B, Yang LP et al.  Structure, function, regulation and polymorphism and the clinical significance of human cytochrome P450 1A2.  Drug Metab Rev  2010;42:268-354.  PubMed
    2. Sachse C, Bhambra U, Smith G et al.  Polymorphisms in the cytochrome P450 CYP1A2 gene (CYP1A2) in colorectal cancer patients and controls: allele frequencies, linkage disequilibrium and influence on caffeine metabolism.  Br J Clin Pharmacol 2003;55:68-76.  PubMed
    3. Sachse C, Brockmoller J, Bauer S et al.  Functional significant of a C->A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine.  Br J Clin Pharmacol  1999;47:445-9. Pubmed
    4. Chida M, Yokoi T, Fukui T et al.  Detection of three genetic polymorphisms in the 5'-flanking region and intron 1 of human CYP1A2 in the Japanese population.  Jpn J Cancer Res 1999;90:899-902.  PubMed
    5. Chen X, Wang L, Zhi L et al.  The G-3113A polymorphism in CYP1A2 affects the caffeine metabolic ratio in Chinese population.  Clin Pharmacol Ther  2005;78:249-59.  PubMed
    6. Pavanello S, Pulliero A, Lupi S et al.  Influence of the genetic polymorphism in the 5'-noncoding region of the CYP1A2 gene on CYP1A2 phenotype and urinary mutagenicity in smokers.  Mutat Res 2005;587:59-66.  PubMed
    7. Akillu E, Carrillo JA, Makonnen E et al. Genetic polymorphism of CYP1A2 in Ethiopians affecting induction and expression: characterization of novel haplotypes with single-nucleotide polymorphisms in intron 1.  Mol Pharmacol 2003;64:659-69.  PubMed  
    8. Zhou SF, Yang LP, Zhou ZW et al.  Insights into the substrate specificity, inhibitors, regulation, and polymorphisms and the clinical impact of human cytochrome P450 1A2.  AAPS J  2009;11:481-94.  PubMed
    9. Huang JD, Guo WC, Lai MD et al.  Detection of a novel cytochrome P-450 1A2 polymorphism (F21L) in Chinese.  Drug Metab Dispos 1999;27:98-101. PubMed
    10. Pucci L, Geppetti A, Maggini V et al.  CYP1A2 F21L and F186L polymorphism in an Italian population sample.  Drug Metab Pharmacokinet  2007;22:220-2.  PubMed
    11. Chevalier D, Cauffiez C, Allorge D, et al. Five novel natural allelic variants—951A>C, 1042G>A (D348N), 1156A>T (I386F), 1217G>A (C406Y) and 1291C>T (C431Y)—of the human CYP1A2 gene in a French Caucasian population. Hum Mutat  2001;17:355-356.  PubMed
    12. Zhou H, Josephy PD, Kim D et al.  Functional characterization of four allelic variants of human cytochrome P450 1A2.  Arch Biochem Biophys 2004;422:23-30.  PubMed
    13. Allorge D, Chevalier D, Lo-Guidice JM et al.  Identification of a novel splice-site mutation in the CYP1A2 gene.  Br J Clin Pharmacol  2003;56:341-4.  PubMed
    14. Soyama A, Saito Y, Hanioka N et al.  Single nucleotide polymorphisms and haplotypes of CYP1A2 in a Japanese population.  Drug Metab Pharmacokinet  2005 20:24-33.  PubMed
    15. Uslu A, Ogus C, Ozdemir T et al.  The effect of CYP1A2 gene polymorphisms on Theophylline metabolism and chronic obstructive pulmonary disease in Turkish patients.  BMB Rep 2010;43:530-4.  PubMed
    16. Shimada T, Yamazaki H, Mimura M et al.Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther  1994;270:414-423.  PubMed

     

Editors & Reviewers

  • Editors:  Anthony J. Busti, MD, PharmD, FNLA, FAHA
    Last Reviewed:  June 2015

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