Interindividual Differences in Hepatic Expression of CYP3A4: Relationship to Genetic Polymorphism in the 5′-Upstream Regulatory Region

Westlind, Anna; Löfberg, Lena; Tindberg, Niclas; Andersson, Tommy; Ingelman‐Sundberg, Magnus

doi:10.1006/bbrc.1999.0752

Cited by 273 publications

(146 citation statements)

References 15 publications

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“…It was observed that the only variation was the A>G mutation at position c.-290 corresponding to CYP3A4-V (25). Our results support those of previous studies indicating that this CYP3A4 gene is highly conserved, and concur with previous data demonstrating that the upstream region is highly preserved (25,40).…”

Section: Discussionsupporting

confidence: 92%

“…Besides analysis using a human liver microsome system, which found no apparent correlation between CYP3A4 genotypes and nifedipine oxidation activity (25), and in vitro tests using a liver, which revealed that CYP3A4*1B has only a moderate effect on mRNA and protein construction (46), there is evidence linking the CYP3A4 polymorphism and CYP3A4 mRNA production and protein expression through clinical approaches. Transcriptional and genotyping analysis using liver samples from 18 Caucasian donors found an association between allelic constitution and CYP3A4 mRNA levels.…”

Section: Discussionmentioning

confidence: 99%

“…The authors concluded that a single base change or single nucleotide polymorphism (SNP) in the 5'-flanking region of the CYP3A4 gene may influence prostate carcinogenesis (16). Following this, the CYP3A4*1B allele was also detected in other studies analyzing genetic polymorphisms in the 5'-upstream regulatory region and hepatic expression of CYP3A4 (25). Sequencing analysis provided additional evidence of this variant in Caucasian, African-American and Chinese individuals (26).…”

Section: D3] Similarmentioning

confidence: 95%

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Unique CYP3A4 genetic variant in Brazilian tuberculosis patients with/without HIV

et al. 2011

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Abstract. CYP3A4 is involved in tuberculosis (TB) and human immunodeficiency virus (HIV) drug metabolism. Transcriptional activation by rifampicin involves the CYP3A4 gene 5'-upstream region. Consequently, variation may interfere with transcription and enzymatic activity and even drug response. However, genetic polymorphisms and distribution of CYP3A4 allelic frequencies in individuals from Rio de Janeiro remain unknown. The aim of this study was to conduct research into sequencing the CYP3A4 5'-upstream region in Brazilian patients with and without HIV. This follow-up study involved 106 individuals undergoing treatment for TB and/ or HIV. The CYP3A4 5'-upstream region was analyzed using PCR, sequencing and clinical data. Male patients revealed a higher HIV frequency (p=0.021). The TB forms observed were pulmonary (48.1%), extrapulmonary (22.64%) and disseminated (27.36%). Lymph node form was the most frequent (70.83%) extrapulmonary form of TB. The only single nucleotide polymorphism detected in the population was c.-392A>G. Genotypes observed were CYP3A4*1A/CYP3A4*1A (45.3%), CYP3A4*1A/CYP3A4*1B (40.6%) and CYP3A4*1B/ CYP3A4*1B (14.2%), revealing a different distribution with extrapulmonary TB cases (17.6% CYP3A4*1A/CYP3A4*1B and 23.5% CYP3A4*1B/CYP3A4*1B). The CYP3A4*1A allele was found to be associated with tobacco use. The CYP3A4*1B mutant allele occurred in 34% of patients. This study revealed that the CYP3A4 5'-upstream regulatory region was highly conserved with the exception of the -392 position. Genotype association with tobacco suggests that CYP3A4 may participate in tobacco metabolism. Genotype distribution inversion in extrapulmonary TB cases suggests that CYP3A4 may be involved in TB prognosis.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: D3] Similarmentioning

confidence: 95%

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Unique CYP3A4 genetic variant in Brazilian tuberculosis patients with/without HIV

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: 98%

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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“…17,31,32 For CYP3A4, which deactivates testosterone, a variant has been identi®ed which has altered testosterone metabolism. 33,34 This variant has the highest frequency in African-Americans, mid-frequency in Caucasians, and lowest frequency in Asians, 35,36 re¯ecting relative prostate cancer rates in these populations. The CYP3A4 variant was associated with prostate cancer risk in Caucasians 23 and African-Americans 36 in case ± control studies.…”

Section: Genes Involved In Androgen Metabolism and Regulation In The mentioning

confidence: 99%

The role of candidate genetic polymorphisms in the etiology of prostate cancer

Neuhausen

2000

Prostate Cancer Prostatic Dis

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Prostate cancer appears to result from complex interactions among genetic, endocrine and environmental factors. Identi®cation of risk factors for development and progression of prostate cancer is needed. This will allow researchers to design strategies to reduce the morbidity and mortality from this cancer and to identify individuals at increased risk of developing the disease. It is probable that common genetic polymorphisms (variants) in genes directly and indirectly involved in androgen biosynthesis, metabolism and regulation are important. Other important genes are likely to be those directly involved in regulation of prostate cell proliferation and apoptosis. Prostate Cancer and Prostatic Diseases (2000) 3, 236±240.

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Interindividual Differences in Hepatic Expression of CYP3A4: Relationship to Genetic Polymorphism in the 5′-Upstream Regulatory Region

Cited by 273 publications

References 15 publications

Unique CYP3A4 genetic variant in Brazilian tuberculosis patients with/without HIV

Unique CYP3A4 genetic variant in Brazilian tuberculosis patients with/without HIV

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

The role of candidate genetic polymorphisms in the etiology of prostate cancer

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