European Journal of Clinical Pharmacology

, Volume 62, Issue 6, pp 417–422

CYP3A phenotypes and genotypes in North Indians

  • Naushad Rais
  • Yogesh K. Chawla
  • Krishan K. Kohli
Pharmacogenetics

Abstract

Objectives

To phenotype 200 healthy North Indians for cytochrome P450 3A (CYP3A) activity by measuring urinary ratio of 6β-OH-cortisol/cortisol (6β-OH-CS/CS) and to genotype the subjects demonstrating low and high CYP3A activity for the presence of CYP3A4*1B, *2, *4, *5, *6 and *10 alleles.

Methods

Morning spot urine samples were collected from 200 healthy North Indians. CS and 6β-OH-CS were extracted and quantified by HPLC. Genotyping was performed by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP).

Results

Urinary 6β-OH-CS/CS ratio demonstrated a mean of 52.0 ± 46 (1.1–290). North Indians demonstrated unimodal distribution with respect to urinary 6β-OH-CS/CS ratio. On the basis of phenotypes, the subjects were divided into three groups demonstrating low (n=50), intermediate (n=100) and high (n=50) CYP3A activity. These groups demonstrated 6β-OH-CS/CS ratio of 13.4 ± 5.2 (1.1–21.0), 40 ± 11.9 (21.2–63.2)  and 114 ± 51.0 (66–290), respectively. One hundred subjects, 50 in the low and 50 in the high activity group, were genotyped for CYP3A4*1B, *2, *4, *5, *6 and *10. Only 2 heterozygotes with genotype CYP3A4*1/*1B were found in the high CYP3A activity group. CYP3A4*2, *4, *5, *6 and *10 were not found in the subjects studied.

Conclusion

This is the first investigation establishing CYP3A phenotypes and demonstrating the absence of common CYP3A4 genotypes in North Indians.

Keywords

Cytochrome P450 3A Genetic polymorphism Pharmacogenetics Pharmacogenomics 

References

  1. 1.
    Tateishi T, Watanabe M, Moriya H, Yamaguchi S, Sato T, Kobayashi S (1999) No ethnic difference between Caucasians and Japanese hepatic samples in the expression frequency of CYP3A5 and CYP3A7 proteins. Biochem Pharmacol 57:935–939PubMedCrossRefGoogle Scholar
  2. 2.
    Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, Watkins PB, Daly A, Wrighton SA, Hall SD, Maurel P, Relling M, Brimer C, Yasuda K, Venkataramanan R, Strom S, Thummel K, Boguski MS, Schuetz E (2001) Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 27:383–391PubMedCrossRefGoogle Scholar
  3. 3.
    Watkins PB (1994) Noninvasive tests of CYP3A enzymes. Pharmacogenetics 4:171–184PubMedCrossRefGoogle Scholar
  4. 4.
    Zaigler M, Tantcheva-Poor I, Fuhr U (2000) Problems and perspectives of phenotyping for drug metabolizing enzymes in man. Int J Clin Pharmacol Ther 38:1–9PubMedGoogle Scholar
  5. 5.
    Westlind A, Lofberg L, Tindberg N, Andersson TB, Ingelman-Sundberg M (1999) Interindividual differences in hepatic expression of CYP3A4: relationship to genetic polymorphism in the 5′- upstream regulatory region. Biochem Biophys Res Comm 259:201–205PubMedCrossRefGoogle Scholar
  6. 6.
    Zhu B, Liu Z-Q, Chen G-L, Chen X-P, Ou-Yang D-S, Wang L-S, Huang S-L, Tan Z-R, Zhou H-H (2003) The distribution and gender difference of CYP3A activity in Chinese subjects. Br J Clin Pharmacol 55:264–269PubMedCrossRefGoogle Scholar
  7. 7.
    Hashimoto H, Toide K, Kitamura R, Fujita M, Tagawa S, Itoh S, Kamataki T (1993) Gene structure of CYP3A4, an adult-specific form of cytochrome P450 in human livers, and its transcriptional control. Eur J Biochem 218:585–595PubMedCrossRefGoogle Scholar
  8. 8.
    Rebbeck TR, Jaffe JM, Walker AH, Wein AJ, Malkowicz SB (1998) Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst 90:1225–1229PubMedCrossRefGoogle Scholar
  9. 9.
    Ball SE, Scatina J, Kao J, Ferron GM, Fruncillo R, Mayer P, Weinryb I, Guida M, Hopkins PJ, Warner N, Hall J (1999) Population distribution and effects on drug metabolism of a genetic variant in the 5′ promoter region of CYP3A4. Clin Pharmacol Ther 66:288–294PubMedCrossRefGoogle Scholar
  10. 10.
    Sata F, Sapone A, Elizondo G, Stocker P, Miller VP, Zheng W, Raunio H, Crespi CL, Gonzalez FJ (2000) CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12: evidence for an allelic variant with altered catalytic activity. Clin Pharmacol Ther 67:48–56PubMedCrossRefGoogle Scholar
  11. 11.
    Hsieh K-P, Lin Y-Y, Cheng C-L, Lai M-L, Lin M-S, Siest J-P, Huang J-D (2001) Novel mutations of CYP3A4 in Chinese. Drug Metab Dispos 29:268–273PubMedGoogle Scholar
  12. 12.
    Eiselt R, Domanski TL, Zibat A, Mueller R, Presecan-Siedal E, Hustert E, Zanger UM, Brockmoller J, Klenk H-P, Meyer UA, Khan KK, He Y-A, Halpert JR, Wojnowski L (2001) Identification and functional characterization of eight CYP3A4 protein variants. Pharmacogenetics 11:447–458PubMedCrossRefGoogle Scholar
  13. 13.
    Lamba JK, Lin YS, Thummel K, Daly A, Watkins PB, Strom S, Zhang J, Schuetz EG (2002) Common allelic variants of cytochrome P4503A4 and their prevalence in different populations. Pharmacogenetics 12:121–132PubMedCrossRefGoogle Scholar
  14. 14.
    Dai D, Tang J, Rose R, Hodgson E, Bienstock RJ, Mohrenweiser HW, Goldstein JA (2001) Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos. J Pharmacol Exper Ther 299:825–831Google Scholar
  15. 15.
    Chowbay B, Cumaraswamy S, Cheung YB, Zhou Q, Lee EJD (2003) Genetic polymorphisms in MDR1 and CYP3A4 genes in Asians and the influence of MDR1 haplotypes on cyclosporin disposition in heart transplant recipients. Pharmacogenetics 13:89–95PubMedCrossRefGoogle Scholar
  16. 16.
    Lamba JK, Dhiman RK, Kohli KK (2000) CYP2C19 genetic mutations in North Indians. Clin Pharmacol Ther 68:328–335PubMedCrossRefGoogle Scholar
  17. 17.
    Adithan C, Gerard N, Vasu S, Rosemary J, Shashindran CH, Krishnamoorthy R (2003) Allele and genotype frequency of CYP2C19 in a Tamilian population. Br J Clin Pharmacol 56:331–333PubMedCrossRefGoogle Scholar
  18. 18.
    Lykkesfeldt J, Loft S, Poulsen HE (1994) Simultaneous determination of urinary free cortisol and 6β-hydroxycortisol by high-performance liquid chromatography to measure human CYP3A activity. J Chromatogr B 660:23–29CrossRefGoogle Scholar
  19. 19.
    Daly AK, Steen VM, Fairbrother KS, Idle JR (1996) CYP2D6 multiallelism. Methods Enzymol 272:199–210PubMedCrossRefGoogle Scholar
  20. 20.
    Ged C, Rouillon JM, Pichard L, Combalbert J, Bressot N, Bories P, Michel H, Beaune P, Maurel P (1989) The increase in urinary excretion of 6β-hydroxycortisol as a marker of human hepatic cytochrome P450IIIA induction. Br J Clin Pharmacol 28:373–387PubMedGoogle Scholar
  21. 21.
    Ozdemir V, Kalow W, Tang B-K, Paterson AD, Walker SE, Endrenyi L, Kashuba ADM (2000) Evaluation of the genetic component of variability in CYP3A4 activity: a repeated drug administration method. Pharmacogenetics 10:373–388PubMedCrossRefGoogle Scholar
  22. 22.
    Kleinbloesem CH, van Brummelen P, Faber H, Danhof M, Vermeulen NPE, Breimer DD (1984) Variability in nifedipine pharmacokinetics and dynamics: A new oxidation polymorphism in man. Biochem Pharmacol 33:3721–3724PubMedCrossRefGoogle Scholar
  23. 23.
    Schellens JHM, Soons PA, Breimer DD (1988) Lack of bimodality in nifedipine plasma kinetics in a large population of healthy subjects. Biochem Pharmacol 37:2507–2510PubMedCrossRefGoogle Scholar
  24. 24.
    Horsmans Y, Desager JP, Harvengt C (1992) Absence of CYP3A genetic polymorphism assesed by urinary excretion of 6β-hydroxycortisol in 102 healthy subjects on rifampicin. Pharmacol Toxicol 71:258–261PubMedCrossRefGoogle Scholar
  25. 25.
    Inagaki K, Inagaki M, Kataoka T, Sekido I, Gill MA, Nishida M (2002) A wide interindividual variability of urinary 6β-hydroxycortisol to free cortisol in 487 healthy Japanese subjects in near basal condition. Ther Drug Monitor 24:722–727CrossRefGoogle Scholar
  26. 26.
    Tateishi T, Watanabe M, Nakura H, Asoh M, Shirai H, Mizorogi Y, Kobayashi S, Thummel KE, Wilkinson GR (2001) CYP3A activity in European American and Japanese men using midazolam as an in vivo probe. Clin Pharmacol Ther 69:333–339PubMedCrossRefGoogle Scholar
  27. 27.
    Yu K-S, Cho J-Y, Shon J-H, Bae K-S, Yi S-Y, Lim H-S, Jang I-J, Shin S-G (2001) Ethnic differences and relationships in the oral pharmacokinetics of nifedipine and erythromycin. Clin Pharmacol Ther 70:228–236PubMedCrossRefGoogle Scholar
  28. 28.
    Haehner BD, Gorski JC, Vandenbranden M, Wrighton SA, Janardan SK, Watkins PB, Hall SD (1996) Bimodal distribution of renal cytochrome P450 3A activity in humans. Mol Pharmacol 50:52–59PubMedGoogle Scholar
  29. 29.
    Hunt CM, Westerkam WR, Stave GM (1992) Effect of age and gender on the activity of human hepatic CYP3A. Biochem Pharmacol 44:275–283PubMedCrossRefGoogle Scholar
  30. 30.
    Watkins PB, Turgeon DK, Saenger P, Lown KS, Kolars JC, Hamilton T, Fishman K, Guzelian PS, Voorhees JJ (1992) Comparison of urinary 6-β-cortisol and the erythromycin breath test as measures of hepatic P450IIIA (CYP3A) activity. Clin Pharmacol Ther 52:265–273PubMedCrossRefGoogle Scholar
  31. 31.
    Ng MCY, Young RP, Critchley JAJH, Leung NWY, Lau JWY, Li AKC (1996) Urinary 6β-hydroxycortisol excretion in Hong Kong Chinese patients with hepatocellular carcinoma and other chronic liver diseases. Cancer 77:1427–1433PubMedCrossRefGoogle Scholar
  32. 32.
    Gorski JC, Vannaprasaht S, Hamman MA, Ambrosius WT, Bruce MA, Haehner-Daniels B, Hall SD (2003) The effect of age, sex, and rifampin administration on intestinal and hepatic cytochrome P450 3A activity. Clin Pharmacol Ther 74:275–287PubMedCrossRefGoogle Scholar
  33. 33.
    Wang A, Yu B-N, Luo C-H, Tan Z-R, Zhou G, Wang L-S, Zhang W, Li Z, Liu J, Zhou H-H (2005) Ile118Val genetic polymorphism of CYP3A4 and its effects on lipid-lowering efficacy of simvastatin in Chinese hyperlipidemic patients. Eur J Clin Pharmacol 60:843–848PubMedCrossRefGoogle Scholar
  34. 34.
    Westlind-Johnsson A, Malmebo S, Johansson A, Otter C, Andersson TB, Johansson I, Edwards RJ, Boobis AR, Ingelman-Sundberg M (2003) Comparative analysis of CYP3A expression in human liver suggests only a minor role for CYP3A5 in drug metabolism. Drug Metab Dispos 31:755–761PubMedCrossRefGoogle Scholar
  35. 35.
    Burk O, Tegude H, Koch I, Hustert E, Wolbold R, Glaeser H, Klein K, Fromm MF, Nuessler AK, Neuhaus P, Zanger UM, Eichelbaum M, Wojnowski L (2002) Molecular mechanisms of polymorphic CYP3A7 expression in adult human liver and intestine. J Biol Chem 277:24280–24288PubMedCrossRefGoogle Scholar
  36. 36.
    Rodriguez-Antona C, Jande M, Rane A, Ingelman-Sundberg M (2005) Identification and phenotype characterization of two CYP3A haplotypes causing different enzymatic capacity in fetal liver. Clin Pharmacol Ther 77:259–270PubMedCrossRefGoogle Scholar
  37. 37.
    Goodwin B, Hodgson E, Liddle C (1999) The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module. Mol Pharmacol 56:1329–1339PubMedGoogle Scholar
  38. 38.
    Goodwin B, Hodgson E, D’Costa DJ, Robertson GR, Liddle C (2002) Transcriptional regulation of the human CYP3A4 gene by the constitutive androstane receptor. Mol Pharmacol 62:359–365PubMedCrossRefGoogle Scholar
  39. 39.
    Lim YP, Liu CH, Shyu LJ, Huang JD (2005) Functional characterization of a novel polymorphism of pregnane X receptor, Q158K, in Chinese subjects. Pharmacogenet Genomics 15:337–341PubMedCrossRefGoogle Scholar
  40. 40.
    Cavalli SA, Hirata MH, Hirata RDC (2001) Detection of Mbo II polymorphism at the 5′ promoter region of CYP3A4. Clin Chem 47:348–351PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Naushad Rais
    • 1
  • Yogesh K. Chawla
    • 2
  • Krishan K. Kohli
    • 1
  1. 1.Department of BiochemistryPostgraduate Institute of Medical Education and ResearchChandigarhIndia
  2. 2.Department of HepatologyPostgraduate Institute of Medical Education and ResearchChandigarhIndia

Personalised recommendations