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Archived Comments for: Coffee consumption and CYP1A2 genotype in relation to bone mineral density of the proximal femur in elderly men and women: a cohort study

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  1. CYP1A2*1F is not a 'rapid metabolizer' phenotype

    Vidya Perera, Faculty of Pharmacy, The University of Sydney

    21 June 2011

    The authors of this study conclude that bone mineral density (BMD) was lower in people who reported having high coffee consumption and also had rapid metabolism of caffeine (defined as having a particular CYP1A2 genotype), indicating `this group' of coffee consumers might be at special risk of bone loss and its associated clinical consequences. However, it is our view that this study does not take into account two critical factors related to CYP1A2 activity that influence the conclusions drawn. Firstly, the CYP1A2 polymorphism (-163 C>A) is associated with higher inducibility only in people who are cigarette smokers and secondly, environmental factors play a major and significant role in determining CYP1A2 activity.

    Hallstrom et al., state that `The C allele at position -163 in the CYP1A2 gene is considered to confer decreased inducibility to the enzyme. Consequently, carriers of a C allele at this position are regarded as 'slow' metabolizers of caffeine'. Numerous studies have demonstrated that this allele (known as CYP1A2*1F) has no association with activity. It is associated with increased induction of CYP1A2 metabolic activity in people who are smokers (when compared to smokers who do not carry this allelic variation) but has no association with activity in non-smokers [2-4]. Furthermore, Hallstrom et al. have not determined CYP1A2 activity in individual subjects by phenotyping but have inferred activity from CYP1A2 genotype. Unlike other drug metabolizing enzymes, such as CYP2D6, where genetic polymorphisms are known to result in rapid and poor metabolizers, no such genotype-phenotype relationship has been demonstrated for CYP1A2 [5]. In contrast to CYP2D6, CYP1A2 is highly inducible by environmental factors. Previous studies have demonstrated that cigarette smoking, ingesting char-grilled meats and the use of oral contraceptives in females result in significant changes in CYP1A2 activity [6]. Interestingly, a recent study by Browning et al., has demonstrated that variability in the CYP1A2 gene is greater than first thought [7]. A number of simple assays and phenotyping protocols are available to measure CYP1A2 activity [8, 9].
    The authors also state that `men who were high consumers of coffee' (defined as more than 4 cups of coffee a day) with `rapid metabolism of caffeine' had lower BMD. A recent study by Djordevic et al., demonstrated that heavy coffee consumption (defined as 3 or more cups of coffee a day) induced CYP1A2 activity suggesting that caffeine induces its own metabolism. Therefore, this subset of the population may be considered `rapid metabolizers' due to the possible induction of CYP1A2 by heavy caffeine consumption. However, this should be confirmed through CYP1A2 phenotyping.

    In conclusion, both genetic and environmental factors play an important role in influencing CYP1A2 activity and should be accounted for in studies linking CYP1A2 activity to health conditions or outcomes using CYP1A2 phenotyping.


    1 Hallstrom H, Melhus H, Glynn A, Lind L, Ann-Christine S, Michaelsson K (2010) Coffee Consumption and CYP1A2 Genotype in Relation to Bone Mineral Density of the Proximal Femur in Elderly Men and Women: A Cohort Study. Nutrition & Metabolism 7 (1): 12

    2 Aklillu E, Carrillo JA, Makonnen E, Hellman K, Pitarque M, Bertilsson L, Ingelman-Sundberg M (2003) Genetic polymorphism of CYP1A2 in Ethiopians affecting induction and expression: characterization of novel haplotypes with single-nucleotide polymorphisms in intron 1. Mol Pharmacol 64 (3): 659-669

    3 Ghotbi R, Christensen M, Roh H-K, Ingelman-Sundberg M, Aklillu E, Bertilsson L (2007) Comparisons of CYP1A2 genetic polymorphisms, enzyme activity and the genotype-phenotype relationship in Swedes and Koreans. Eur J Clin Pharmacol 63 (6): 537-546

    4 Sachse C, Bhambra U, Smith G, Lightfoot TJ, Barrett JH, Scollay J, Garner RC, Boobis AR, Wolf CR, Gooderham NJ, Colorectal Cancer Study G (2003) Polymorphisms in the cytochrome P450 CYP1A2 gene (CYP1A2) in colorectal cancer patients and controls: allele frequencies, linkage disequilibrium and influence on caffeine metabolism. British Journal of Clinical Pharmacology 55 (1): 68-76

    5 Ingelman-Sundberg M, Sim SC, Gomez A, Rodrigues AD (2007) Influence of cytochrome P450 polymorphisms on drug therapies: Pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacology & Therapeutics 116: 496-526

    6 Le Marchand L, Franke AA, Custer L, Wilkens LR, Cooney RV (1997) Lifestyle and nutritional correlates of cytochrome CYP1A2 activity: inverse associations with plasma lutein and alpha-tocopherol. Pharmacogenetics 7 (1): 11-19

    7 Browning SL, Tarekegn A, Bekele E, Bradman N, Thomas MG (2010) CYP1A2 is more variable than previously thought: a genomic biography of the gene behind the human drug-metabolizing enzyme. Pharmacogenetics and Genomics 20 (11): 647-664

    8 Perera V, McLachlan AJ, Gross AS (2010) Caffeine and paraxanthine HPLC assay for CYP1A2 phenotype assessment using saliva and plasma. Biomed Chromatogr 24 (10): 1136-1144

    9 Perera V, McLachlan AJ, Gross AS (2010) Pharmacokinetics of Caffeine and Paraxanthine in Plasma and Saliva in Healthy Volunteers. In Preparation

    Competing interests