Identification and characterization of CYP3A4*20, a novel rare CYP3A4 allele without functional activity

Westlind‐Johnsson, Anna; Hermann, Róbert; Huennemeyer, Andreas; Hauns, B; Lahu, Gëzim; Nassr, Nassr; Zech, K.; Ingelman‐Sundberg, Magnus; Richter, Oliver von

doi:10.1016/j.clpt.2005.11.015

Cited by 107 publications

(81 citation statements)

References 39 publications

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“…Four variants, two in the exon (CYP3A4*6, *18) and two in the intron, were identified in the direct DNA sequencing. The frequency of alleles with coding SNPs (from CYP3A4*2 to CYP3A4*20) was Ͻ5% in all of the ethnic groups studied (Eiselt et al, 2001;Hsieh et al, 2001;Lamba et al, 2002b;Cavaco et al, 2003;Fukushima-Uesaka et al, 2004;Westlind-Johnsson et al, 2006). Despite their low frequencies, certain allelic variants have been observed exclusively in a specific subset of ethnic groups.…”

Section: Discussionmentioning

confidence: 99%

“…To our knowledge, the present study is the first to evaluate the effect of CYP3A4*18 on therapeutic drug disposition in humans. Recently, it has been reported that CYP3A4*20 exhibits a clear genotype-phenotype correlation with MDZ pharmacokinetics (Westlind-Johnsson et al, 2006). MDZ has been reported to be extensively metabolized by CYP3A in the liver and intestine (Thummel and Wilkinson, 1998) but is not a substrate for P-glycoprotein (Kim et al, 1999).…”

Section: Effects Of Cyp3a4*18 On Midazolam Dispositionmentioning

confidence: 99%

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TheCYP3A4^*18Allele, the Most Frequent Coding Variant in Asian Populations, Does Not Significantly Affect the Midazolam Disposition in Heterozygous Individuals

Lee¹,

Lee²,

Jeong³

et al. 2007

Drug Metab Dispos

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ABSTRACT:The objective of this study was to identify CYP3A4 variants in Koreans and to characterize their functional consequences in vitro and in vivo. Four single nucleotide polymorphisms were identified in 50 Koreans by direct DNA sequencing. In an additional genotyping using 248 subjects, CYP3A4*18 was confirmed as the most frequent coding variant in Koreans at 1.7%, and its frequency was similar to that of Asians, suggesting that CYP3A4*18 would be the highest coding variant in Asians. The recombinant CYP3A4.18 protein prepared in baculovirus expression system showed 67.4% lower V max and 1.8-fold higher K m for midazolam 1-hydroxylation compared with the wild type. The mean values of C max and area under the concentration curve (AUC) in the CYP3A4*1/*18 and CYP3A5*1/*3 subjects (n ‫؍‬ 8) were 63% and 32% higher than in CYP3A4*1/*1 and CYP3A5*1/*3 carriers (n ‫؍‬ 8), respectively. Although the in vitro assay exhibited a significant reduction of the enzyme activity for midazolam, the in vivo differences associated with the CYP3A4*1/*18 tend to be low (P < 0.07 in C max and P < 0.09 in AUC). In summary, the heterozygous CYP3A4*1/*18 does not appear to cause a significant change of midazolam disposition in vivo; however, the clinical relevance of CYP3A4*18/*18 remains to be evaluated.CYP3A is the most abundantly expressed subfamily of cytochrome P450 (P450) enzymes in the human liver (Shimada et al., 1994). The CYP3A enzymes are responsible for the metabolism of more than 50% of clinically used drugs (Komori et al., 1990;Guengerich, 1999;Lamba et al., 2002a). Four human CYP3A enzymes, CYP3A4, CYP3A5, CYP3A7, and CYP3A43, have been identified. CYP3A4 is regarded as the most dominant CYP3A enzyme in the liver and small intestine of humans. It has been reported that CYP3A4 expression shows large interindividual variation (Guengerich, 1999;Ozdemir et al., 2000;Lin et al., 2002). These variations can lead to different responses to human drugs that are substrates for CYP3A4. Because approximately 85% of this variability is attributed to genetic factors (Ozdemir et al., 2000), genetic analysis is needed to understand interindividual variability. To date, more than 39 allelic variants have been described (http://www.cypalleles.ki.se/cyp3a4.htm) (Dai et al., 2001;Eiselt et al., 2001;Kuehl et al., 2001;Lamba et al., 2002a;Fukushima-Uesaka et al., 2004). Among the CYP3A4 variants, alleles with nonsynonymous single nucleotide polymorphisms (SNPs), i.e., CYP3A4*2, *4, *5, *6, *17, and *18, have been shown to alter enzyme activity, compared with the wild type (Lee and Goldstein, 2005). Although some CYP3A SNPs exhibited an altered intrinsic clearance of CYP3A substrates in vitro, there have been few data explaining their meaningful influences on its substrate clearance in humans. The CYP3A4*1B promoter SNP has been extensively studied because of its role in transcriptional regulation in vitro. However, no significant change associated with CYP3A4*1B was observed in midazolam (MDZ) clearance (Wandel et al., 2000;Garcia-Martin...

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Section: Discussionmentioning

confidence: 99%

Section: Effects Of Cyp3a4*18 On Midazolam Dispositionmentioning

confidence: 99%

TheCYP3A4^*18Allele, the Most Frequent Coding Variant in Asian Populations, Does Not Significantly Affect the Midazolam Disposition in Heterozygous Individuals

Lee¹,

Lee²,

Jeong³

et al. 2007

Drug Metab Dispos

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“…This polymorphism has, however, not been investigated in relation to Tac dose requirement nor toxicity. [121,122] In conclusion, ethnic variation in the prevalence of CYP3A5, CYP3A4, and ABCB1 genotypes is high and clinically relevant. Given the fact that CYP3A5 genotype has the strongest and most consistent association with Tac dose requirement, a CYP3A5 genotype-based Tac dosing approach may be especially relevant for patients of African descent who are more often CYP3A5 expressers than Caucasians.…”

Section: Ethnic Considerationsmentioning

confidence: 99%

Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations

Tang

Andrews

Gelder

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

117

114

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Introduction: Tacrolimus (Tac) is effective in preventing acute rejection but has considerable toxicity and inter-individual variability in pharmacokinetics and pharmacodynamics. Part of this is explained by polymorphisms in genes encoding Tac-metabolizing enzymes and transporters. A better understanding of Tac pharmacokinetics and pharmacodynamics may help to minimize different outcomes amongst transplant recipients by personalizing immunosuppression. Areas covered: The pharmacogenetic contribution of Tac metabolism will be examined, with a focus on recent discoveries, new developments and ethnic considerations. Expert opinion: The strongest and most consistent association in pharmacogenetics is between the CYP3A5 genotype and Tac dose requirement, with CYP3A5 expressers having a~40-50% higher dose requirement compared to non-expressers. Two recent randomized-controlled clinical trials using CYP3A5 genotype, however, did not show a decrease in acute rejections nor reduced toxicity. CYP3A4*22, CYP3A4*26, and POR*28 are also associated with Tac dose requirements and may be included to provide the expected improvement of Tac therapy. Studies focusing on the intracellular drug concentrations and on calcineurin inhibitor-induced nephrotoxicity also seem promising. For all studies, however, the ethnic prevalence of genotypes should be taken into account, as this may significantly impact the effect of pre-emptive genotyping.ARTICLE HISTORY

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“…However, transgenic CYP3A4 knockout mice develop endocrine alterations (Yu et al, 2005) and specific functions of possible endocrine character during some phase of human development, which could explain the degree of conservation, cannot be excluded. At present only one subject with a true defective CYP3A4 allele has been documented, where the capacity for midazolam hydroxylation was severely decreased (Westlind-Johnsson et al, 2006). CYP1B1 represents a special case where several rare defective alleles have been identified and their occurrence associated to glaucoma, and, in addition, many common variant haplotypes with missense mutations are distributed in the population, but their functional consequences are less pronounced.…”

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confidence: 99%

Cytochrome P450 pharmacogenetics and cancer

2006

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The cytochromes P450 (CYPs) are key enzymes in cancer formation and cancer treatment. They mediate the metabolic activation of numerous precarcinogens and participate in the inactivation and activation of anticancer drugs. Since all CYPs that metabolize xenobiotics are polymorphic, much emphasis has been put on the investigation of a relationship between the distribution of specific variant CYP alleles and risk for different types of cancer, but a consistent view does not yet exist. This is to a great extent explained by the fact that the CYPs involved in activation of precarcinogens are in general not functionally polymorphic. This is in contrast to CYPs that are active in drug biotransformation where large interindividual differences in the capacity to metabolize therapeutic drugs are seen as a consequence of polymorphic alleles with altered function. This includes also some anticancer drugs like tamoxifen and cyclophosphamide metabolized by CYP2D6, CYP2C19 and CYP2B6. Some P450 forms are also selectively expressed in tumours, and this could provide a mechanism for drug resistance, but also future therapies using these enzymes as drug targets can be envisioned. This review gives an upto-date description of our current knowledge in these areas.

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Identification and characterization of CYP3A4*20, a novel rare CYP3A4 allele without functional activity

Cited by 107 publications

References 39 publications

TheCYP3A4^*18Allele, the Most Frequent Coding Variant in Asian Populations, Does Not Significantly Affect the Midazolam Disposition in Heterozygous Individuals

TheCYP3A4^*18Allele, the Most Frequent Coding Variant in Asian Populations, Does Not Significantly Affect the Midazolam Disposition in Heterozygous Individuals

Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations

Cytochrome P450 pharmacogenetics and cancer

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Identification and characterization of CYP3A4*20, a novel rare CYP3A4 allele without functional activity

Cited by 107 publications

References 39 publications

TheCYP3A4*18Allele, the Most Frequent Coding Variant in Asian Populations, Does Not Significantly Affect the Midazolam Disposition in Heterozygous Individuals

TheCYP3A4*18Allele, the Most Frequent Coding Variant in Asian Populations, Does Not Significantly Affect the Midazolam Disposition in Heterozygous Individuals

Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations

Cytochrome P450 pharmacogenetics and cancer

Contact Info

Product

Resources

About

TheCYP3A4^*18Allele, the Most Frequent Coding Variant in Asian Populations, Does Not Significantly Affect the Midazolam Disposition in Heterozygous Individuals

TheCYP3A4^*18Allele, the Most Frequent Coding Variant in Asian Populations, Does Not Significantly Affect the Midazolam Disposition in Heterozygous Individuals