Abstract
To clarify partly inconsistent results in gene expression of cytochromes P450 (CYP) in the circulation, we undertook a systematic study over a long time period in 19 healthy men and women. CYP specific mRNA for 1A2, 1B1, 2E1 and 3A4 was studied in the leukocytes collected repeatedly on 20 occasions over a 10-week period. Our study revealed a varying pattern of CYP expression over time. CYP3A4 specific mRNA exhibited the largest intra-individual variation with an average coefficient of variation between 40 and 250%. CYP1B1 and CYP2E1 did not vary as much (39–110%). CYP1A2 was sporadically detected in only ten individuals, but varied considerably when measurable (61–256%). The expression in CYP1B1 was significantly higher in women than in men (P = 0.02). We conclude that CYP gene expression in blood varies considerably over time. It is conceivable that the variation reflects a hitherto unknown influence of exogenous or endogenous factors such as hormones, cytokines, and other circulating factors on the hematogeneous cytochromes.
Similar content being viewed by others
References
Meyer UA . Overview of enzymes of drug metabolism J Pharmacokin Biopharmaceut 1996 24: 449–459
de Wildt SN, Kearns GL, Leeder JS, van den Anker JN . Cytochrome P450 3A: ontogeny and drug disposition Clin Pharmacokinet 1999 37: 485–505
Kivistö KT, Griese E-U, Fritz P, Linder A, Hakkola J, Raunio H et al . Expression of cytochrome P450 3A enzymes in human lung: a combined RT-PCR and immunohistochemical analysis of normal tissue and lung tumours Naunyn-Schmiedeberg's Arch Pharmacol 1996 353: 207–212
Raucy JL, Ingelman-Sundberg M, Carpenter S, Rannug A, Rane A, Franklin M et al . Drug metabolizing enzymes in lymphocytes J Biochem Mol Toxicol 1999 13: 223–226
Ingelman-Sundberg M, Oscarson M, McLellan RA . Polymorphic human cytochrome P450 enzymes: an opportunity for individualized drug treatment Trends Pharmacol Sci 1999 20: 342–349
Why bother about cytochrome P450 enzymes? Drug Ther Bull 2000 38: 93–95
Andersen MR, Farin FM, Omiecinski CJ . Quantification of multiple human cytochrome P450 mRNA molecules using competitive reverse transcriptase-PCR DNA Cell Biol 1998 17: 231–238
Finnström N, Bjelfman C, Thörn M, Lööf L, Rane A . Quantitation of cytochrome P450 mRNAs in patients with suspected liver diseases as assessed by reverse transcriptase-PCR J Lab Clin Med 1999 134: 133–140
Finnström N, Thörn M, Lööf L, Rane A . Independent patterns of cytochrome P450 gene expression in human blood and liver Eur J Clin Pharm 2001 57: 403–409
Kellermann G, Luyten-Kellermann M, Shaw C . Metabolism of polycyclic aromatic hydrocarbons in cultured human leukocytes under genetic control Humangenetik 1973 20: 257–263
Tortora GJ, Grabowski SR . Leukocytes (white blood cells). In: Roesch B (ed) Principles of Anatomy and Physiology HarperCollins: New York 1996 562–565
Rane A, Finnström N, Lind A-B . Expression of human cytochrome P450 in blood element In: 12th International Symposium on Microsomes and Drug Oxidation, Montpellier, France 1998
Bruguerolle B, Toumi M, Faraj F, Vervloet D, Razzouk H . Influence of the menstrual cycle on theophylline pharmacokinetics in asthmatics Eur J Clin Pharmacol 1990 39: 59–61
Lane JD, Steege JF, Rupp SL, Kuhn CM . Menstrual cycle effects on caffeine elimination in the human female Eur J Clin Pharmacol 1992 43: 543–546
Shavit G, Lerman P, Korczyn AD, Kivity S, Bechar M, Gitter S . Phenytoin pharmacokinetics in catamenial epilepsy Neurology 1984 34: 959–961
Kashuba AD, Bertino JS Jr, Rocci ML Jr, Kulawy RW, Beck DJ, Nafziger AN . Quantification of 3-month intraindividual variability and the influence of sex and menstrual cycle phase on CYP3A activity as measured by phenotyping with intravenous midazolam Clin Pharmacol Ther 1998 64: 269–277
Kashuba AD, Bertino JS Jr, Kearns GL, Leeder JS, James AW, Gotschall R et al . Quantitation of three-month intraindividual variability and influence of sex and menstrual cycle phase on CYP1A2, N-acetyltransferase-2, and xanthine oxidase activity determined with caffeine phenotyping Clin Pharmacol Ther 1998 63: 540–551
Kharasch ED, Russell M, Garton K, Lentz G, Bowdle TA, Cox K . Assessment of cytochrome P450 3A4 activity during the menstrual cycle using alfentanil as a noninvasive probe Anesthesiology 1997 87: 26–35
Zaigler M, Rietbrock S, Szymanski J, Dericks-Tan JS, Staib AH, Fuhr U . Variation of CYP1A2-dependent caffeine metabolism during menstrual cycle in healthy women Int J Clin Pharmacol Ther 2000 38: 235–244
Gerdin E, Rane A . N-demethylation of ethylmorphine in pregnant and non-pregnant women and in men: an evaluation of the effects of sex steroids Br J Clin Pharmacol 1992 34: 250–255
Baron JM, Zwadlo-Klarwasser G, Jugert F, Hamann W, Rubben A, Mukhtar H et al . Cytochrome P450 1B1: a major P450 isoenzyme in human blood monocytes and macrophage subsets Biochem Pharmacol 1998 56: 1105–1110
Dassi C, Signorini S, Gerthoux P, Cazzaniga M, Brambilla P . Cytochrome P450 1B1 mRNA measured in blood mononuclear cells by quantitative reverse transcription-PCR Clin Chem 1998 44: 2416–2421
Hayes CL, Spink DC, Spink BC, Cao JQ, Walker NJ, Sutter TR . 17b-estradiol hydroxylation catalyzed by human cytochrome P450 1B1 Proc Natl Acad Sci USA 1996 93: 9776–9781
Rasmussen BB, Brosen K . Determination of urinary metabolites of caffeine for the assessment of cytochrome P4501A2, xanthine oxidase, and N-acetyltransferase activity in humans Ther Drug Monit 1996 18: 254–262
Relling MV, Lin JS, Ayers GD, Evans WE . Racial and gender differences in N-acetyltransferase, xanthine oxidase, and CYP1A2 activities Clin Pharmacol Ther 1992 52: 643–658
Spatzenegger M, Horsmans Y, Verbeeck RK . CYP1A1 but not CYP1A2 proteins are expressed in human lymphocytes Pharmacol Toxicol 2000 86: 242–244
Janardan SK, Lown KS, Schmiedlin-Ren P, Thummel KE, Watkins PB . Selective expression of CYP3A5 and not CYP3A4 in human blood Pharmacogenetics 1996 6: 379–385
Raucy JL, Curley G, Carpenter SP . Use of lymphocytes for assessing ethanol-mediated alterations in the expression of the hepatic cytochrome P4502E1 Alcoholism: Clin Exp Res 1995 19: 1369–1375
Raucy JL, Schultz ED, Wester MR, Arora S, Johnston DE, Omdahl JL et al . Human lymphocyte cytochrome P450 2E1, a putative marker for alcohol-mediated changes in hepatic chlorzoxazone activity Drug Metab Dispos 1997 25: 1429–1435
Acknowledgements
Research nurses Katarina Andersson and Annelie Wahlberg are kindly acknowledged for their excellence in taking care of the volunteers and the samples. Dr Stefan Lundgren is acknowledged for valuable scientific discussions. This study was supported by grants from the Swedish Medical Research Council (04496 and 3902).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Finnström, N., Ask, B., Dahl, ML. et al. Intra-individual variation and sex differences in gene expression of cytochromes P450 in circulating leukocytes. Pharmacogenomics J 2, 111–116 (2002). https://doi.org/10.1038/sj.tpj.6500086
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.tpj.6500086
- Springer Nature Limited
Keywords
This article is cited by
-
Gender-specific changes in energy metabolism and protein degradation as major pathways affected in livers of mice treated with ibuprofen
Scientific Reports (2020)
-
Factors affecting the anthelmintic efficacy of papaya latex in vivo: host sex and intensity of infection
Parasitology Research (2015)
-
Effect of CYP3A4*22, CYP3A5*3, and CYP3A Combined Genotypes on Cyclosporine, Everolimus, and Tacrolimus Pharmacokinetics in Renal Transplantation
CPT: Pharmacometrics & Systems Pharmacology (2014)
-
Three polymorphisms in cytochrome P450 1B1 (CYP1B1) gene and breast cancer risk: a meta-analysis
Breast Cancer Research and Treatment (2010)
-
Tobacco use induces anti-apoptotic, proliferative patterns of gene expression in circulating leukocytes of Caucasian males
BMC Medical Genomics (2008)