Population distribution and effects on drug metabolism of a genetic variant in the 5′ promotor region of CYP3A4

Ball, S.; Scatina, JoAnn; Kao, John Y.; Ferron, Géraldine M.; Fruncillo, Richard J.; Mayer, Philip; Weinryb, Ira; Guida, Marco; Hopkins, Penelope J.; Warner, Natalie J.; Hall, Jeff

doi:10.1016/s0009-9236(99)70037-8

Cited by 217 publications

(131 citation statements)

References 28 publications

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“…Comparing the frequency of the G allele (0.15) with those reported by other studies, we see a similarity with Brazilian population (0.13) (Cavalli et al), Asian (0.16) (Thompson et al) and Hispanic (0.09) (Ball et al, 1999), and the frequency of the mutant variant CYP3A4*1B was significantly higher than that observed in Europeans (0.05) (Sata et al, 2000) and American population, both white (0.04) and Black (0.54) (Ball et al) and lower in Africans (0.82) (Zanger et al, 2008) and Afro-American (0.67) (Sata et al). Gao et al (2008) demonstrated an association between the presence of G allele in hypercholesterolemic individuals who had a greater reduction of total cholesterol levels, when treated with atorvastatin 20 mg/day for 4 weeks in Asiatic population.…”

Section: Discussionsupporting

confidence: 82%

Frequency of Common Variants in Genes Involved in Lipid-Lowering Response to Statins in Chilean Subjects with Hypercholesterolemia

et al. 2011

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SUMMARY: Interindividual differences in activity and expression of the metabolizing enzymes cytochrome P450 (CYP) 3A4 and 3A5 and the multidrug efflux pump P-glycoprotein (P-gp, encoded by ABCB1 gene) contribute considerably to lipid-lowering efficacy of statin treatment in subjects with hypercholesterolemia. Variability in the activity of CYP3A4, CYP3A5 and P-gp could be considered to result from genetic polymorphisms encoding their genes. However, the available data indicate that the frequencies of ABCB1, CYP3A4 and CYP3A5 gene polymorphisms differ significantly across populations. Thus, the aim of the present study was to determine the allelic frequency of three common variants of these genes in Chilean individuals with primary hypercholesterolemia (HC) and controls. A total of 135 unrelated patients (44 ± 7 years old) with diagnosis of hypercholesterolemia (Total cholesterol ≥ 240 mg/dL) and 120 normolipidemic healthy controls (40 ± 10 years old; total cholesterol ≤ 200 mg/dL) were included in this study. The 3435C>T (MDR1), -290A>G (CYP3A4) and 6986A>G (CYP3A5) gene polymorphisms were analyzed by PCR-RFLP. The genotype distribution for 3435C>T variant of ABCB1 in HC patients (CC: 49%, CT: 37%, TT: 14%) and controls (CC: 41%, CT: 48%, TT: 11%) was comparable (P=0.186). Similarly, the genotype distribution for -290A>G polymorphism of CYP3A4 in HC subjects (AA: 73%, AG: 27%, GG: 0%) and controls (AA: 71%, AG: 29%, GG: 0%) was equivalent (P = 0.863). Finally, the genotype distribution for 6986A>G variant of CYP3A5 in HC individuals (AA: 4%, AG: 41%, GG: 55%) and controls (AA: 4%, AG: 47%, GG: 49%) was similar (P=0.594). The allelic frequencies of 3435C>T (ABCB1), -290A>G (CYP3A4) and 6986A>G (CYP3A5) polymorphisms are similar between Chilean HC patients and controls, and comparable to frequencies found in Asian populations.

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Section: Discussionsupporting

confidence: 82%

Frequency of Common Variants in Genes Involved in Lipid-Lowering Response to Statins in Chilean Subjects with Hypercholesterolemia

et al. 2011

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“…The rs2740574 SNP is in the promoter region of the gene, but efforts to show a functional effect of this variant have proved difficult. Spurdle et al (2002) evaluated multiple reporter gene constructs, but found no differences in the transcription between the putative disease and wild-type allele; the results of other functional studies have been equivocal (Ball et al, 1999;Westlind et al, 1999;Amirimani et al, 2003;Rodriguez-Antona et al, 2005). Alternatively, it may be that rs2740574 is simply in linkage disequilibrium with the causal variant, which remains to be identified.…”

Section: Discussionmentioning

confidence: 97%

Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium

Pearce¹,

Near²,

Berg³

et al. 2009

Br J Cancer

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The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at Pp0.10 in a log-additive model: rs2740574 in CYP3A4 (P ¼ 0.011), rs1805386 in LIG4 (P ¼ 0.007), and rs3218536 in XRCC2 (P ¼ 0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR homozygous(hom) ¼ 2.50 (95% CI 0.54-11.57, P ¼ 0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20 -6.56, P ¼ 0.017, p het across studies ¼ 0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

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“…However, a polymorphism, which plays a significant role in the activity of CYP3A4, has not yet been identified in the 5 0 -regulatory region of the CYP3A4 gene. 24 Therefore, we have focused on human PXR (hPXR) as a factor effecting CYP3A expression and identified splicing variants of hPXR as a possible factor in interindividual variation caused in CYP3A activity. 25 Interestingly, we have found that mRNA expression of wild-type hPXR is well correlated with mRNA expression of CYP3A4 in liver sample (unpublished data), which is consistent with the recent report.…”

Section: Discussionmentioning

confidence: 99%

CYP3A5 genotype did not impact on nifedipine disposition in healthy volunteers

et al. 2003

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CYP3A5 expression is regulated by single-nucleotide polymorphisms (SNPs). The CYP3A5 genotype might contribute to a marked interindividual variation in CYP3A-mediated metabolism of drugs. Nifedipine is a typical substrate of CYP3A4 and CYP3A5 in vitro. The aim of this study was to elucidate the influence of the CYP3A5 genotype on nifedipine disposition in healthy subjects. A single capsule containing 10 mg of nifedipine was administered to 16 healthy male Japanese subjects (eight subjects: CYP3A5*1/*3; eight subjects: CYP3A5*3/*3). Blood samples were collected to analyze the pharmacokinetics of serum nifedipine and nitropyridine metabolite (M-I). The area under the plasma concentration-time curve (AUC), the peak plasma concentration (C max ) and the terminal half-life (t 1/2 ) of nifedipine, and the ratio of the nifedipine AUC to M-I AUC showed large intragroup variations, but no significant differences between the two genotypes. Based on the present findings, the functional relevance of CYP3A5 polymorphism should be re-evaluated in clinical trials. 2 Recently, single-nucleotide polymorphisms (SNPs) were identified in intron 3 (A-G: CYP3A5*3) and exon 7 (G-A: CYP3A5*6) of the CYP3A5 gene.3 In addition, CYP3A5*5 and CYP3A5*7 were reported as a defective allele of CYP3A5, which gave a substantial impact on CYP3A5 expression. 4,5 These SNPs cause a frame-shift mutation or alternative splicing and protein truncation, and result in the absence of CYP3A5, suggesting that only people with at least one CYP3A5*1 allele express large amounts of CYP3A5 protein. Therefore, these findings suggest that polymorphic CYP3A5 expression might be one factor contributing to the marked interindividual variation observed in CYP3A-mediated metabolism of drugs.We previously reported the frequencies of CYP3A5-related SNPs in 200 healthy Japanese subjects. 6 As a result, the allele frequency of CYP3A5*3 was approximately 70%, but CYP3A5*6 was not detected in the Japanese population. Accordingly, these findings suggested that about 40% of Japanese express relatively high levels of metabolically active CYP3A5 protein.

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Population distribution and effects on drug metabolism of a genetic variant in the 5′ promotor region of CYP3A4

Abstract: This promotor region polymorphism does not appear to play a major role in determining constitutive CYP3A4 expression.

Cited by 217 publications

References 28 publications

Frequency of Common Variants in Genes Involved in Lipid-Lowering Response to Statins in Chilean Subjects with Hypercholesterolemia

Frequency of Common Variants in Genes Involved in Lipid-Lowering Response to Statins in Chilean Subjects with Hypercholesterolemia

Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium

CYP3A5 genotype did not impact on nifedipine disposition in healthy volunteers

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