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

  • Pharmacogenetics
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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.

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References

  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 90:1871–1878

    Google Scholar 

  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 2:47–52

    Google Scholar 

  3. Guengerich FP (1999) Cytochrome P-450 3A4: regulation and role in drug metabolism. Annu Rev Pharmacol Toxicol 39:1–17

    Article  Google Scholar 

  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 29:133–140

    Google Scholar 

  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 25:502–507

    Google Scholar 

  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 10:373–388

    Article  CAS  PubMed  Google Scholar 

  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 66:288–294

    Google Scholar 

  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 90:1225–1229

    Article  Google Scholar 

  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 67:48–56

    Article  Google Scholar 

  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):268–273

    Google Scholar 

  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 11:447–458

    Article  Google Scholar 

  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 12:121–132

    Article  CAS  PubMed  Google Scholar 

  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 299:825–831

    Google Scholar 

  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 25:1191–1199

    Google Scholar 

  15. Vickers S, Duncan CA, Chen I-W, Rosegay A, Duggan DE (1990) Metabolic disposition studies of simvastatin, a cholesterollowering prodrug. Drug Metab Dispos 18:138–145

    Google Scholar 

  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 50:209–215

    Article  Google Scholar 

  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 70:546–551

    Google Scholar 

  18. Nordin C, Dahl ML, Eriksson M, Sjoberg S (1997) Is the cholesterollowering effect of simvastatin influenced by CYP2D6 polymorphism? Lancet 350:29–30

    Article  Google Scholar 

  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):595–596

    Google Scholar 

  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 56:120–124

    Article  Google Scholar 

  21. Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: a laboratory manual, 2nd edn.Cold Spring Harbor Laboratory, Cold Spring Harbor, pp16–19

    Google Scholar 

  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 48:1511–1519

    Google Scholar 

  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 B793:357–366

    Article  Google Scholar 

  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 28:373–387

    Google Scholar 

  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 26:229–233

    Google Scholar 

  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 28:51–57

    Google Scholar 

  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 39:487–494

    Google Scholar 

  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 31:1283–1287

    Google Scholar 

  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 91:1588–1590

    Article  Google Scholar 

  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 91:1587–1590

    Article  Google Scholar 

  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 259:201–205

    Article  CAS  PubMed  Google Scholar 

  32. Mauro VF (1993) Clinical pharmacokinetics and practical applications of simvastatin. Clin Pharmacokinet 24:195–202

    Google Scholar 

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Acknowledgements

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

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Correspondence to Hong-Hao Zhou.

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Wang, A., Yu, BN., Luo, CH. et al. Ile118Val genetic polymorphism of CYP3A4 and its effects on lipid-lowering efficacy of simvastatin in Chinese hyperlipidemic patients. Eur J Clin Pharmacol 60, 843–848 (2005). https://doi.org/10.1007/s00228-004-0848-7

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  • DOI: https://doi.org/10.1007/s00228-004-0848-7

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