Representation of CYP3A4, CYP3A5 and UGT1A4 Polymorphisms within Croatian Breast Cancer Patients’ Population

Bojanić, Kristina; Kuna, Lucija; Bilić-Ćurčić, Ines; Wagner, Jasenka; Stoehr, Robert; Kralik, Kristina; Kizivat, Tomislav; Ivanac, Gordana; Včev, Aleksandar; Wu, George Y.; Smolić, Martina

doi:10.3390/ijerph17103692

Cited by 5 publications

(4 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…No ADRs have been associated with other SNPs (rs4646, rs10046, rs727479, rs1062033) [141]. The CYP3A4*1B, CYP3A5*3 and UGT1A4*2 variants may influence the onset of ADRs in women with estrogen receptor (ER)-positive breast cancer treated with anastrozole [142].…”

Section: Cancermentioning

confidence: 99%

Genophenotypic Factors and Pharmacogenomics in Adverse Drug Reactions

Cacabelos

Naidoo

Corzo

et al. 2021

IJMS

View full text Add to dashboard Cite

Adverse drug reactions (ADRs) rank as one of the top 10 leading causes of death and illness in developed countries. ADRs show differential features depending upon genotype, age, sex, race, pathology, drug category, route of administration, and drug–drug interactions. Pharmacogenomics (PGx) provides the physician effective clues for optimizing drug efficacy and safety in major problems of health such as cardiovascular disease and associated disorders, cancer and brain disorders. Important aspects to be considered are also the impact of immunopharmacogenomics in cutaneous ADRs as well as the influence of genomic factors associated with COVID-19 and vaccination strategies. Major limitations for the routine use of PGx procedures for ADRs prevention are the lack of education and training in physicians and pharmacists, poor characterization of drug-related PGx, unspecific biomarkers of drug efficacy and toxicity, cost-effectiveness, administrative problems in health organizations, and insufficient regulation for the generalized use of PGx in the clinical setting. The implementation of PGx requires: (i) education of physicians and all other parties involved in the use and benefits of PGx; (ii) prospective studies to demonstrate the benefits of PGx genotyping; (iii) standardization of PGx procedures and development of clinical guidelines; (iv) NGS and microarrays to cover genes with high PGx potential; and (v) new regulations for PGx-related drug development and PGx drug labelling.

show abstract

Section: Cancermentioning

confidence: 99%

Genophenotypic Factors and Pharmacogenomics in Adverse Drug Reactions

Cacabelos

Naidoo

Corzo

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…Our study revealed strong LD between CYP3A4*1.001 and CYP3A5*1 [4,24], CYP3A4*1.001 and CYP3A5*3 [25][26][27], or CYP3A4*22 and CYP3A5*3. However, the effect of CYP3A4*1.001 is not influenced by CYP3A5, C0/D being significantly reduced in CYP35, independently of the CYP3A4 variant [18,28].…”

Section: Discussionmentioning

confidence: 48%

Single Nucleotide Polymorphisms of CYP3A4 and CYP3A5 in Romanian Kidney Transplant Recipients: Effect on Tacrolimus Pharmacokinetics in a Single-Center Experience

Rotarescu,

Maruntelu,

Rotarescu

et al. 2024

JCM

View full text Add to dashboard Cite

Background: This study examines the impact of CYP3A4 and CYP 3A5 genotypes on tacrolimus (Tac) pharmacokinetics in Romanian kidney transplanted patients. Methods: We included 112 kidney recipients genotyped for CYP3A5*3, CYP3A4*1.001, and CYP3A4*22. Patients were categorized into poor, intermediate, rapid, and ultra-rapid metabolizers based on the functional defects linked to CYP3A variants. Results: Predominantly male (63.4%) with an average age of 40.58 years, the cohort exhibited a high prevalence of the CYP3A4*1/*1 (86.6%) and CYP3A5*3/*3 (77.7%) genotypes. CYP3A4*1.001 and CYP3A5*1 alleles significantly influenced the Tac concentration-to-dose (C0/D) ratio in various post-transplant periods, while the CYP3A4*22 allele showed no such effect (p = 0.016, p < 0.001). Stepwise regression highlighted the CYP3A4*1.001’s impact in early post-transplant phases, with hematocrit and age also influencing Tac variability. Conclusions: The study indicates a complex interaction of CYP3A4 and CYP3A5 genotypes on Tac metabolism, suggesting the necessity for personalized medication approaches based on genetic profiling in kidney transplant recipients.

show abstract

“…However, individuals homozygous for UGT1A4 48 Val had significantly lower mean concentrations of 4-OH-TAM-O-Gluc and endoxifen-Gluc than wt/wt plus wt/48Val subjects. Low activity of trans-4-hydroxytamoxifen glucuronidation was also observed in carriers of the UGT1A4 24Thr/48Leu allele [4,8,18].…”

Section: Results Discussionmentioning

confidence: 85%

“…UGT2B7 demonstrated the highest affinity and activity for trans-4-hydroxytamoxifen [ 26,16,30]. The UGT1A4 gene encodes an enzyme that catalyzes the formation of a glucuronide bound by quaternary ammonium to TAM [4,7,8,18]. Two unlinked m issense polymorphisms were identified in this gene: in codon 24 Pro>Thr (rs6755571) and in codon 48 Leu>Val (rs2011425).…”

Section: Results Discussionmentioning

confidence: 99%

Influence of polymorphism of enzymes of the UDP family-glucuronyl transferases on the biotransformation of tamoxifen in the therapy of luminal forms of breast cancer

Yurchenko,

Shkarupa,

Kachula

et al. 2023

Rep. of Vinnytsia Nation. Med. Univ.

View full text Add to dashboard Cite

Annotation. Tamoxifen (TAM) (1-[4-(2-dimethylaminoethoxy)-phenyl]-1,2-diphenylbut-1(Z)-ene) is a non-steroidal selective estrogen receptor modulator (SERM), which is recognized as the "gold standard" of hormone therapy for estrogen-dependent breast cancer (BC). It is known that adjuvant treatment with TAM increases recurrence-free survival and overall survival in patients with hormone-receptor-positive breast cancer. Also, tamoxifen manifests itself as a partial estrogen agonist, which can be associated with the development of complications such as endometrial cancer, venous thromboembolism, etc. The presence of resistance and relapses during TAM therapy, which reach up to 30%, remains an actual problem. Therefore, studying the mechanisms underlying the individualization of both therapeutic effect and toxicity associated with TAM remains an important challenge. In the detoxification of both TAM and its active metabolites, glucuronidation processes, which belong to the second phase of biotransformation of xenobiotics and actively take place in the liver as well as in the mammary gland, play an important role, and therefore the study of this process can contribute to the understanding of the interindividual variability of the therapeutic effect and toxicity of TAM. The aim – to analyze the data of the scientific literature on the study of the influence of glucuronyltransferase (UGT) enzymes and their polymorphic forms on the biotransformation of TAM and its active metabolites in the treatment of hormone-receptor-positive breast cancer. A retrospective analysis of the literature of scientific databases Scopus, Web of Science, PubMed., MedLines for 2013-2023 was carried out. It is possible to draw the following conclusions that UGT isozymes are responsible for the conjugation and detoxification of tamoxifen and its metabolites in the form of glucuronides 4-OH-tamoxifen-N-glucuronide, 4-OH-tamoxifen-O-glucuronide and endoxifen-O-glucuronide. UGT1A8, UGT1A10, UGT2B7, UGT2B15 and UGT2B17 isoforms played the greatest role in glucuronidation of tamoxifen and its active metabolites, but UGT1A4 was recognized as the main one. Depending on the content of active TAM metabolites and their glucuronides in the blood plasma, it can be stated that carriers of the UGT2B15 Lys523Thr and UGT2B17del alleles demonstrated increased enzyme activity, and individuals with one variant UGT2B15 523Thr allele can even be considered superactive metabolizers of 4-OH-tamoxifen-O- glucuronide and endoxifen-glucuronide. Also, high levels of 4-OH-tamoxifen-N-glucuronide were observed in carriers of the allele of the UGT2B17del genotype. Carriers of the above alleles have high activity of glucuronidation processes and low levels of active metabolites of TAM, which calls into question the rationality of prescribing TAM as hormone therapy. In contrast, patients with UGT1A4 48Val, UGT2B7 268Tyr alleles, or with wild-type genotypes for UGT2B17 nodel and UGT2B15 523Lys, will have high levels of active metabolites and are the group of choice for tamoxifen therapy in estrogen-receptor-positive breast cancer because they will have a low rate of glucuronidation and detoxification. However, in order to create a system of clinical algorithms for the formation of tamoxifen-sensitive groups of patients, further detailed study of other possibilities of the biotransformation system in the metabolism of tamoxifen is required.

show abstract

Representation of CYP3A4, CYP3A5 and UGT1A4 Polymorphisms within Croatian Breast Cancer Patients’ Population

Cited by 5 publications

References 44 publications

Genophenotypic Factors and Pharmacogenomics in Adverse Drug Reactions

Genophenotypic Factors and Pharmacogenomics in Adverse Drug Reactions

Single Nucleotide Polymorphisms of CYP3A4 and CYP3A5 in Romanian Kidney Transplant Recipients: Effect on Tacrolimus Pharmacokinetics in a Single-Center Experience

Influence of polymorphism of enzymes of the UDP family-glucuronyl transferases on the biotransformation of tamoxifen in the therapy of luminal forms of breast cancer

Contact Info

Product

Resources

About