Advertisement

European Journal of Clinical Pharmacology

, Volume 60, Issue 12, pp 843–848 | Cite as

Ile118Val genetic polymorphism of CYP3A4 and its effects on lipid-lowering efficacy of simvastatin in Chinese hyperlipidemic patients

  • An Wang
  • Bang-Ning Yu
  • Chen-Hui Luo
  • Zhi-Rong Tan
  • Gan Zhou
  • Lian-Sheng Wang
  • Wei Zhang
  • Zhi Li
  • Jie Liu
  • Hong-Hao ZhouEmail author
Pharmacogenetics

Abstract

Objectives

To determine the frequencies of CYP3A4 alleles (CYP3A4*4,*5 and *6) in Chinese hyperlipidemic patients and to observe the impact of CYP3A4*4 (Ile118Val) genetic polymorphism on the lipid-lowering effects of simvastatin and on the activity of CYP3A4.

Methods

From hospitalized and non-hospitalized patients, 211 unrelated hyperlipidemic patients were recruited for genotyping. CYP3A4 genotypes were determined by means of polymerase chain reaction and restriction fragment length polymorphism analysis. Of the non-hospitalized hyperlipidemic patients, 8 with CYP3A4*1/*1 and 8 with CYP3A4*1/*4 genotypes were selected to be treated with 20 mg simvastatin daily for 4 weeks. Serum triglycerides (TG), cholesterol (CHO) and low-density lipoprotein (LDL) levels were determined using an automated analyzer (Hitachi 747, Boehringer Mannheim, Mannheim, Germany). CYP3A4 activity was determined by the ratio of 6-hydroxycortisol to free cortisol (6-OHC/FC) in the morning spot urine with a high-throughput liquid chromatography–tandem mass spectrometry method.

Results

Of 211 subjects, 14 (allele frequency 3.32%) were heterozygous for CYP3A4*4 (Ile118Val). Nevertheless, no subjects with a CYP3A4*5 or CYP3A4*6 allele or homozygous for CYP3A4*4 were identified. The ratio of 6β-OHC/FC was 9.9±13.7 and 56.6±35.7 in subjects with the Ile118Val variant (n=8) and in CYP3A4 wild-type subjects (n=8), respectively (P=0.0039). After oral intake of simvastatin 20 mg daily for 4 weeks, the change of serum lipids in CYP3A4*1/*1 and CYP3A4*1/*4 groups showed a significant difference, with a mean decrease in triglycerides and total cholesterol of 38.1±7.6% versus 25.1±8.3% (P=0.034) and of 35.8±9.6% versus 22.0±20.4% (P=0.0015) (means ± SD), respectively. We found no statistically significant difference in the reductions of LDL between subjects carrying the *1 and *4 genotypes (29.0±7.4% versus 36.8±8.8%, P=0.0721).

Conclusions

The allele frequency of CYP3A4*4 was 3.32% among the hyperlipidemic patients from the Chinese mainland. CYP3A4*4 was an allelic variant related to a functional decrease of CYP3A4 activity, and *4 expression seemed to increase the lipid-lowering effects of simvastatin.

Keywords

Simvastatin Felodipine CYP3A4 Activity Hyperlipidemic Patient CYP2D6 Polymorphism 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

All authors have no conflict of interest. A project supported by the National Science Foundation of China grants F30130210.

References

  1. 1.
    Kolars JC, Schmiedlin-Ren P, Schuetz JD, Fang C, Watkins PB (1992) Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J Clin Invest 90:1871–1878Google Scholar
  2. 2.
    Boxenbaum H (1999) Cytochrome P450 3A4 in vivo ketoconazole competitive inhibition: determination of Ki and dangers associated with high clearance drugs in general. J Pharm Pharm Sci 2:47–52Google Scholar
  3. 3.
    Guengerich FP (1999) Cytochrome P-450 3A4: regulation and role in drug metabolism. Annu Rev Pharmacol Toxicol 39:1–17CrossRefGoogle Scholar
  4. 4.
    Hesse LM, Venkatakrishnan K, von Moltke LL, Shader RI, Greenblatt DJ (2001) CYP3A4 is the major CYP isoform mediating the in vitro hydroxylation and demethylation of flunitrazepam. Drug Metab Dispos 29:133–140Google Scholar
  5. 5.
    Wang RW, Newton DJ, Scheri TD, Lu AY (1997) Human cytochrome P450 3A4-catalyzed testosterone 6 beta- hydroxylation and erythromycin N-demethylation. Competition during catalysis. Drug Metab Dispos 25:502–507Google Scholar
  6. 6.
    Ozdemir V, Kalow W, Tang B-K, Paterson AD, Walker SE, Endrenyi L et al (2000) Evaluation of the genetic component of variability in CYP3A4 activity: a repeated drug administration method. Pharmacogenetics 10:373–388CrossRefPubMedGoogle Scholar
  7. 7.
    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 66:288–294Google 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 90:1225–1229CrossRefGoogle Scholar
  9. 9.
    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 67:48–56CrossRefGoogle Scholar
  10. 10.
    Kun-Pin H, Yen-Yu L, Ching-Ling C, Ming-Liang L, Min-Shung L, Jean-Pascal S, Jin-Ding H (2001) Novel Mutations of CYP3A4 in Chinese. Drug Metab Dispos 29(3):268–273Google Scholar
  11. 11.
    Eiselt R, Domanski TL, Zibat A, Mueller R, Presecan- Siedel E, Hustert E, Zanger UM, Brockmoller J, Klenk HP, Meyer UA, Khan KK, He YA, Halpert JR, Wojnow-ski L (2001) Identification and functional characterization of eight CYP3A4 protein variants. Pharmacogenetics 11:447–458CrossRefGoogle Scholar
  12. 12.
    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 12:121–132CrossRefPubMedGoogle Scholar
  13. 13.
    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 Exp Ther 299:825–831Google Scholar
  14. 14.
    Prueksaritanont T, Gorham LM, Ma B et al (1997) In vitro metabolism of simvastatin in humans: identification of metabolizing enzymes and effect of the drug on hepatic P450s. Drug Metab Dispos 25:1191–1199Google Scholar
  15. 15.
    Vickers S, Duncan CA, Chen I-W, Rosegay A, Duggan DE (1990) Metabolic disposition studies of simvastatin, a cholesterollowering prodrug. Drug Metab Dispos 18:138–145Google Scholar
  16. 16.
    Transon C, Leeman T, Dayer P (1996) In vitro comparative inhibition profiles of major drug metabolising cytochrome P450 isoenzymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors. Eur J Clin Pharmacol 50:209–215CrossRefGoogle Scholar
  17. 17.
    Mulder AB, van Lijf HJ, Bon MA, van den Bergh FA, Touw DJ, Neef C, et al (2001) Association of polymorphism in the cytochrome CYP2D6 and the efficacy and tolerability of simvastatin. Clin Pharmacol Ther 70:546–551Google Scholar
  18. 18.
    Nordin C, Dahl ML, Eriksson M, Sjoberg S (1997) Is the cholesterollowering effect of simvastatin influenced by CYP2D6 polymorphism? Lancet 350:29–30CrossRefGoogle Scholar
  19. 19.
    Geisel J, Kivistö KT, Griese EU, Eichelbaum M (2002) The efficacy of simvastatin is not influenced by CYP2D6 polymorphism. Clin Pharmacol Ther 72(5):595–596Google Scholar
  20. 20.
    Prueksaritanont T, Ma B, Yu N (2003) The human hepatic metabolism of simvastatin hydroxy acid is mediated primarily by CYP3A, and not CYP2D6. Br J Clin Pharmacol 56:120–124CrossRefGoogle Scholar
  21. 21.
    Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: a laboratory manual, 2nd edn.Cold Spring Harbor Laboratory, Cold Spring Harbor, pp16–19Google Scholar
  22. 22.
    Taylor RL, Machacek D, Singh RJ (2002) Validation of a high-throughput liquid chromatography–tandem mass spectrometry method for urinary cortisol and cortisone. Clin Chem 48:1511–1519Google Scholar
  23. 23.
    Rouits E, Boisdron-Celle M, Morel A, Gamelin E (2003) Simple and sensitive high-performance liquid chromatography method for simultaneous determination of urinary free cortisol and 6β-hydroxycortisol in routine practice For CYP 3A4 activity evaluation in basal conditions and after grapefruit juice intake. J Chromatogr B793:357–366CrossRefGoogle Scholar
  24. 24.
    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 28:373–387Google Scholar
  25. 25.
    Monsarrat B, Chatelut E, Royer I, Alvinerie P, Dubois J, Dezeuse A, Roche H, Cros S, Wright M, Canal P (1998) Modification of paclitaxel metabolism in a cancer patient by induction of cytochrome P450 3A4. Drug Metab Dispos 26:229–233Google Scholar
  26. 26.
    Pichard-Garcia L, Hyland R, Baulieu J, Fabre J-M, Milton A, Maurel P (2000) Human hepatocytes in primary culture predict lack of cytochrome P-450 3A4 induction by eletriptan in vivo. Drug Metab Dispos 28:51–57Google Scholar
  27. 27.
    Tran JQ, Kovacs SJ, McIntosh TS, Davis HM, Martin DE (1999) Morning spot and 24 hour urinary 6 beta-hydroxycortisol to cortisol ratios: Intra-individual variability and correlation under basal conditions and conditions of CYP 3A4 induction. J Clin Pharmacol 39:487–494Google Scholar
  28. 28.
    Furuta T, Suzuki A, Mori C, Shibasaki H, Yokokawa A, Kasuya Y (2003) Evidence for the validity of cortisol 6β-hydroxylation clearance as a new index for in vivo cytochrome P450 3A phenotyping in humans drug metabolism and disposition. J Chromatogr B 31:1283–1287Google Scholar
  29. 29.
    Amirimani B, Walker AH, Weber BL, Rebbeck TR (1999) RESPONSE: re: modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst 91:1588–1590CrossRefGoogle Scholar
  30. 30.
    Ando Y, Tateishi T, Sekido Y, Yamamoto T, Satoh T, Hasegawa Y, Kobayashi S, Katsumata Y, Shimokata K, Saito H (1999) Re: modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4 [letter; comment]. J Natl Cancer Inst 91:1587–1590CrossRefGoogle Scholar
  31. 31.
    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 Commun 259:201–205CrossRefPubMedGoogle Scholar
  32. 32.
    Mauro VF (1993) Clinical pharmacokinetics and practical applications of simvastatin. Clin Pharmacokinet 24:195–202Google Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • An Wang
    • 1
    • 2
  • Bang-Ning Yu
    • 1
  • Chen-Hui Luo
    • 1
  • Zhi-Rong Tan
    • 1
  • Gan Zhou
    • 1
  • Lian-Sheng Wang
    • 1
  • Wei Zhang
    • 1
  • Zhi Li
    • 1
  • Jie Liu
    • 1
  • Hong-Hao Zhou
    • 1
    Email author
  1. 1.Pharmacogenetics Research Institute, Institute of Clinical PharmacologyCentral South UniversityChangshaChina
  2. 2.Department of Health Toxicology, School of Public HealthCentral South UniversityChangshaChina

Personalised recommendations