Cyp3a5 Genetic Polymorphisms in Different Ethnic Populations

Roy, Jean; Lajoie, Julie; Zijenah, Lynn S.; Barama, Azemi; Poirier, Charles; Ward, Brian J.; Roger, Michel

doi:10.1124/dmd.105.003822

Cited by 150 publications

(99 citation statements)

References 9 publications

(21 reference statements)

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“…Similar to CYP3A5*6, it is found only in populations of African origin (Zimbabwean, 10% and African-American, 10%), not in Caucasian and Asian populations. [22] The CYP3A5*8 variant, presenting a substitution of nucleotide C to T, leads to an amino acid change from arginine to cysteine at codon 28. [13] It was first observed in African-American (4%), but the frequencies in other ethnic groups have not yet been revealed.…”

Section: Genetic Polymorphism Of Cyp3a5mentioning

confidence: 99%

CYP3A5^3*Polymorphism and Its Clinical Implications and Pharmacokinetic Role

Park

Jung

Kim

2014

Transl Clin Pharmacol

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The cytochrome P450 (CYP) 3A subfamily is estimated to participate in the biotransformation of 50% of the currently prescribed drugs. Four members of the CYP3A subfamily have been identified in humans: CYP3A4, CYP3A5, CYP3A7, and CYP3A43. Initial data suggested that CYP3A5 accounts for only a small proportion of the total hepatic CYP3A in about 20% of samples, but it was later revealed that CYP3A5 represents more than 50% of the total CYP3A amount in some individuals. Several genetic variants have been described for the CYP3A5 gene, of which the CYP3A5*3 allele (gA6986G), the most common form and leading to the loss of CYP3A5 activity, has been extensively investigated in the aspect of pharmacokinetics and disease risk. This review summarized the molecular characteristics of the CYP3A5 gene, and discusses the association of the CYP3A5*3 polymorphism with disease risks such as cancer and hypertension, along with its role in the pharmacokinetics of CYP3A substrates.

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Section: Genetic Polymorphism Of Cyp3a5mentioning

confidence: 99%

CYP3A5^3*Polymorphism and Its Clinical Implications and Pharmacokinetic Role

Park

Jung

Kim

2014

Transl Clin Pharmacol

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“…A total of 228 healthy subjects and 165 breast cancer patients were screened for the following polymorphisms: CYP2D6 [*2 (2850C>T; rs16947), *2A (-1584C>G), *3 (2549delA; rs35742686), *4 (1846G>A; rs3892097), *5 (CYP2D6del), *6 (1707delT; rs5030655), *7 (2935A>C; rs5030867), *8 (1758G>T), *9 (2615-2617delAAG; rs5030656), *10 (100C>T; rs1065852), *12 (124G>A; rs5030862), *14 (1758G>A), *17 (1023C>T; rs28371706), *29 (1659G>A; rs61736512), *41 (2988G>A; rs28371725) and *xN (CYP2D6dup)], CYP3A5*3 (6986A>G; rs776746), CYP2C9 [*2 (430C>T; rs1799853) and *3 (1075A>C; rs1057910)] and CYP2C19 [*2 (681G>A; rs4244285), *3 (636G>A; rs4986893) and *17 (-3402C>T and -806C>T; rs12248560)].The polymorphisms in CYP2D6 were genotyped using the INFINITI™ CYP450 2D6I assay (AutoGenomics, Inc.) in accordance with the manufacturer's protocol. The polymorphic variants in CYP3A5, CYP2C9 and CYP2C19 were genotyped by amplification via polymerase chain reaction [24,25], followed by purification by treatment with shrimp alkaline phosphatase and exonuclease I and direct sequencing on a ABI 3730 DNA Analyzer (Applied Biosystems, Inc.).…”

Section: Pharmacogenetic Analysesmentioning

confidence: 99%

Impact of CYP2D6, CYP3A5, CYP2C9 and CYP2C19 polymorphisms on tamoxifen pharmacokinetics in Asian breast cancer patients

Lim

Chen

Singh

et al. 2011

Brit J Clinical Pharma

110

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Tamoxifen is metabolized to active metabolites, 4‐hydroxytamoxifen and endoxifen, by multiple cytochrome P450 (CYP) enzymes including CYP2D6, CYP3A4/5, CYP2C9/19, CYP1A2 and CYP2B6.• The steady‐state plasma concentrations of tamoxifen and its metabolites can be affected by variations in the activity of these enzymes.• Although CYP2D6*4 and *10 have been shown to influence the plasma concentration of endoxifen in Caucasian and Korean patients respectively, there is still a paucity of data on CYP2D6 pharmacogenetics in other Orientals such as Chinese, Malays and Indians.WHAT THIS STUDY ADDS• Pharmacogenetic analyses of a comprehensive panel of CYP2D6 polymorphisms (*2, *2A, *3, *4, *5, *6, *7, *8, *9, *10, *12, *14, *17, *29, *41 and *xN) were performed in three distinct Asian ethnic groups and breast cancer patients with CYP2D6*5 and *10 found to be highly prevalent.• Both CYP2D6*5 and *10 were significantly associated with lower endoxifen and higher N‐desmethyltamoxifen concentrations as well as a lower rate of metabolic conversion of N‐desmethyltamoxifen to endoxifen.• Polymorphisms present in CYP3A5, CYP2C9 and CYP2C19 were not found to be significantly associated with plasma concentrations of analytes suggesting that these enzymes may be playing minor roles in the metabolic pathway of tamoxifen compared with CYP2D6.AIM To investigate the impact of genetic polymorphisms in CYP2D6, CYP3A5, CYP2C9 and CYP2C19 on the pharmacokinetics of tamoxifen and its metabolites in Asian breast cancer patients.METHODS A total of 165 Asian breast cancer patients receiving 20 mg tamoxifen daily and 228 healthy Asian subjects (Chinese, Malay and Indian; n= 76 each) were recruited. The steady‐state plasma concentrations of tamoxifen and its metabolites were quantified using high‐performance liquid chromatography. The CYP2D6 polymorphisms were genotyped using the INFINITI™ CYP450 2D6I assay, while the polymorphisms in CYP3A5, CYP2C9 and CYP2C19 were determined via direct sequencing.RESULTS The polymorphisms, CYP2D6*5 and *10, were significantly associated with lower endoxifen and higher N‐desmethyltamoxifen (NDM) concentrations. Patients who were *1/*1 carriers exhibited 2.4‐ to 2.6‐fold higher endoxifen concentrations and 1.9‐ to 2.1‐fold lower NDM concentrations than either *10/*10 or *5/*10 carriers (P < 0.001). Similarly, the endoxifen concentrations were found to be 1.8‐ to 2.6‐times higher in *1/*5 or *1/*10 carriers compared with *10/*10 and *5/*10 carriers (P≤ 0.001). Similar relationships were observed between the CYP2D6 polymorphisms and metabolic ratios of tamoxifen and its metabolites. No significant associations were observed with regards to the polymorphisms in CYP3A5, CYP2C9 and CYP2C19.CONCLUSIONS The present study in Asian breast cancer patients showed that CYP2D6*5/*10 and *10/*10 genotypes are associated with significantly lower concentrations of the active metabolite of tamoxifen, endoxifen. Identifying such patients before the start of treatment may be useful in optimizing therapy with tamoxifen. The role of CYP3A5, CYP2C9 and CYP2C19 seem to be minor.

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“…Structurally, CYP3A5 is similar to CYP3A4 but the substrate selectivity of these proteins differ (51, 56Á58). CYP3A5*1 is present in approximately 10Á20% of WhiteEuropean individuals (50) and is present in approximately 55% of African American individuals (51,56,59). Apart from the liver, CYP3A5 is also distributed in the intestine and kidneys (50, 60Á62).…”

Section: Cyp3a4 and Cyp3a5mentioning

confidence: 99%

Genetics of antipsychotic drug outcome and implications for the clinician: into the limelight

Changasi

Shams

Pouget

et al. 2014

Translational Developmental Psychiatry

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Background and purpose: Antipsychotics (APs) are the primary method of treatment for schizophrenia and other psychotic disorders. Unfortunately, lengthy trial-and-error approaches are typically required to find the optimal medication and dosage due to a large interindividual variability with outcome to AP treatment. The literature has shown abundant evidence for a genetic component in individuals' responses to APs. Pharmacogenetic studies analyze specific genetic markers and their association with symptom improvement and occurrence of side effects with APs. This research aims to optimize AP drug treatment by usage of predictive testing and to personalize medicine. Recent findings: This review will highlight the most consistent findings in pharmacogenetics of APs and will update the reader on the clinical implications. This will include how genetic variants modulate AP drug levels, side effects, and therapeutic symptom improvement (i.e. response) to AP treatment. Summary: Several promising findings were obtained implicating gene variants of the dopamine receptor genes in addition to gene variants of serotonin receptors for response and common side effects. Notably, effect sizes appear to be particularly high in the genetics of side effects compared to response. One example is antipsychotic-induced weight gain where the leptin, HTR2C and in particular the melanocortin-4-receptor (MC4R) genes have been implicated in weight gain in children and adolescents. Consistent findings were also obtained for genes implicated in tardive dyskinesia and agranulocytosis. However, the most clinically relevant findings pertain to genes involved in drug metabolism such as the CYP2D6 and CYP2C19 genes which have been included in the first genetic test kits such as the Amplichip †

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Cyp3a5 Genetic Polymorphisms in Different Ethnic Populations

Cited by 150 publications

References 9 publications

CYP3A5^3*Polymorphism and Its Clinical Implications and Pharmacokinetic Role

CYP3A5^3*Polymorphism and Its Clinical Implications and Pharmacokinetic Role

Impact of CYP2D6, CYP3A5, CYP2C9 and CYP2C19 polymorphisms on tamoxifen pharmacokinetics in Asian breast cancer patients

Genetics of antipsychotic drug outcome and implications for the clinician: into the limelight

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Cyp3a5 Genetic Polymorphisms in Different Ethnic Populations

Cited by 150 publications

References 9 publications

CYP3A5*3Polymorphism and Its Clinical Implications and Pharmacokinetic Role

CYP3A5*3Polymorphism and Its Clinical Implications and Pharmacokinetic Role

Impact of CYP2D6, CYP3A5, CYP2C9 and CYP2C19 polymorphisms on tamoxifen pharmacokinetics in Asian breast cancer patients

Genetics of antipsychotic drug outcome and implications for the clinician: into the limelight

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Product

Resources

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CYP3A5^3*Polymorphism and Its Clinical Implications and Pharmacokinetic Role

CYP3A5^3*Polymorphism and Its Clinical Implications and Pharmacokinetic Role