Curr Issues Mol Biol. 2022 Aug 1;44(8):3455-3464. doi: 10.3390/cimb44080238.

ABSTRACT

The genetic factors of adult acute lymphoblastic leukemia (ALL) development are only partially understood. The Runt-Related Transcription Factor (RUNX) gene family play a crucial role in hematological malignancies, serving both a tumor suppressor and promoter function. The aim of this study was the assessment of relative RUNX1 and RUNX3 genes expression level among adult ALL cases and a geographically and ethnically matched control group. The relative RUNX1 and RUNX3 genes expression level was assessed by qPCR. The investigated group comprised 60 adult patients newly diagnosed with ALL. The obtained results were compared with a group of 40 healthy individuals, as well as clinical and hematological parameters of patients, and submitted for statistical analysis. ALL patients tend to have significantly higher RUNX1 gene expression level compared with controls. This observation is also true for risk group stratification where high-risk (HR) patients presented higher levels of RUNX1. A higher RUNX1 transcript level correlates with greater leukocytosis while RUNX3 expression is reduced in Philadelphia chromosome bearers. The conducted study sustains the hypothesis that both a reduction and increase in the transcript level of RUNX family genes may be involved in leukemia pathogenesis, although their interaction is complex. In this context, overexpression of the RUNX1 gene in adult ALL cases in particular seems interesting. Obtained results should be interpreted with caution. Further analysis in this research field is needed.

PMID:36005134 | DOI:10.3390/cimb44080238

Pharmacogenomics. 2022 Aug 25. doi: 10.2217/pgs-2022-0105. Online ahead of print.

NO ABSTRACT

PMID:36004680 | DOI:10.2217/pgs-2022-0105

Pharmacogenomics. 2022 Aug 25. doi: 10.2217/pgs-2022-0067. Online ahead of print.

ABSTRACT

Tweetable abstract It is well accepted that pharmacogenomics (PGx) information from Asia and Europe should not be applied to Africa. More work is needed on different ethnic groups to generate population-specific algorithms that can be used effectively and safely.

PMID:36004679 | DOI:10.2217/pgs-2022-0067

Cell Cycle. 2022 Aug 24:1-15. doi: 10.1080/15384101.2022.2109362. Online ahead of print.

ABSTRACT

High-grade serous ovarian cancer (HGSOC) is the most common and malignant type of ovarian cancer, accounting for 70%-80% of mortality. However, the treatment of HGSOC has improved little in the past few decades. Metformin is the first-line medication for the treatment of type 2 diabetes and has now gained more attention in cancer treatment. In this study, we sought to identify potential hub genes that metformin could target in the treatment of HGSOC. We downloaded GSE69428 and GSE69429 in the Gene Expression Omnibus database and performed the bioinformatics analysis. Subsequently, we analyzed the effect of Metformin in HGSOC through biological experiments. Molecular simulation docking was used to predict the interaction of Metformin and CCNE1. We chose CCNE1 for the study based on bioinformatics analysis, literature studies, and preliminary data. We evaluated that CCNE1 is overexpressed in HGSOC tissues and found that HGSOC cells with high CCNE1 expression increase sensitivity to Metformin treatment in the analysis of cell proliferation and anchorage-independent growth. Metformin could inhibit the expression of CCNE1, which is associated with the anti-proliferative effect of tumor cells. Moreover, Metformin could ameliorate the tumor growth in syngeneic orthotopic transplantation mouse models and xenograft tumorigenesis models. Furthermore, molecular simulation docking showed that Metformin may bind to CCNE1 protein, suggesting that CCNE1 could be a potential target for Metformin. Our data revealed that Metformin has antitumor effects on ovarian cancer and CCNE1 could be a potential target for Metformin.

PMID:36004387 | DOI:10.1080/15384101.2022.2109362

Front Pharmacol. 2022 Aug 8;13:891838. doi: 10.3389/fphar.2022.891838. eCollection 2022.

ABSTRACT

Human leukocyte antigen (HLA) proteins are present at the cellular surface of antigen-presenting cells and play a crucial role in the adaptive immune response. Class I genes, specifically certain HLA-B alleles, are associated with adverse drug reactions (ADRs) and are used as pharmacogenetic markers. Although ADRs are a common causes of hospitalization and mortality, the data on the prevalence of HLA-B pharmacogenetics markers in Arab countries are scarce. In this study, we investigated the frequencies of major HLA-B pharmacogenomics markers in the Qatari population. Next-generation sequencing data from 1,098 Qatari individuals were employed for HLA-B typing using HLA-HD version 1.4.0 and IPD-IMGT/HLA database. In addition, HLA-B pharmacogenetics markers were obtained from the HLA Adverse Drug Reaction Database. In total, 469 major HLA-B pharmacogenetic markers were identified, with HLA-B*51:01 being the most frequent pharmacogenetic marker (26.67%) in the Qatari population. Moreover, HLA-B*51:01 is associated with phenytoin- and clindamycin-induced ADRs. The second most frequent pharmacogenetic marker was the HLA-B*58:01 allele (6.56%), which is associated with allopurinol-induced ADRs. The third most frequent pharmacogenetic marker was the HLA-B*44:03 allele, which is associated with phenytoin-induced ADRs. The establishment of a pharmacogenetics screening program in Qatar for cost effective interventions aimed at preventing drug-induced hypersensitivity can be aided by the highly prevalent HLA-B pharmacogenetic markers detected here.

PMID:36003520 | PMC:PMC9393242 | DOI:10.3389/fphar.2022.891838

Clin Pharmacol Ther. 2022 Aug 24. doi: 10.1002/cpt.2730. Online ahead of print.

ABSTRACT

Thiopurine dose optimization by thiopurine-S-methyltransferase (TPMT) or nudix hydrolase-15 (NUDT15) significantly reduced the early leucopenia in Asia. However, it fails to avoid the late incidence (> 2 months). Although 6-thioguanine nucleotides (6TGN) was a makeshift in European, its function is controversial. In the present study, we aimed to explore whether DNA-thioguanine nucleotides (DNA-TG) in leukocytes, compared to 6TGN in erythrocytes, can be a better biomarker for late leucopenia. This was a prospective, observational study. Patients with inflammatory bowel disease (IBD) prescribed thiopurine from February 2019 to December 2019 were recruited. Thiopurine dose was optimized by NUDT15 C415T (rs116855232). DNA-TG and 6TGN levels were determined at the time of late leucopenia or 2 months after the stable dose obtained. A total of 308 patients were included. Thiopurine induced late leucopenia (WBC<3.5×109 /L) were observed in 43 patients (14.0%), who had significantly higher DNA-TG concentration than those without leucopenia (P=3.2×10-9, 423.3 (342.2~565.7) vs 270.5 (188.1~394.3) fmol/μg DNA). No difference of 6TGN concentrations between leucopenia and non-leucopenia was found. With a DNA-TG threshold of 340.1 fmol/μg DNA, 83.7% of leucopenia cases could be identified. Multivariate analysis showed DNA-TG was an independent risk factor for late leucopenia. Quantification of DNA-TG, rather than 6TGN, can be applied to gauge thiopurine therapy after NUDT15 screening in Chinese patients with IBD.

PMID:36002392 | DOI:10.1002/cpt.2730

Drug Metab Pers Ther. 2022 Aug 24. doi: 10.1515/dmpt-2022-0117. Online ahead of print.

ABSTRACT

OBJECTIVES: Timolol maleate is used for the treatment of glaucoma and metabolized by cytochrome CYP2D6 in the liver. The aim of this study was the evaluation of the influence of CYP2D6*4 and CYP2D6*10 gene polymorphisms on the safety of medications containing 0.5% of timolol maleate as glaucoma treatment in patients with primary open-angle glaucoma (POAG).

METHODS: 105 patients with POAG were prescribed glaucoma medications, containing 0.5% timolol maleate. The safety of glaucoma treatment was determined by electrocardiography (ECG) (to assess heart rate (HR) and PQ interval) and blood pressure (BP) measurements. The real-time polymerase chain reaction method was used for the detection of single nucleotide polymorphisms (SNP).

RESULTS: The risk of adverse drug reactions was higher in patients with the CYP2D6*4 GA genotype compared with GG: mean HR change at 1 month (2.88 ± 4.68 and 6.44 ± 5.57, p<0.001) and 6 months (5.14 ± 8.93 and 7.88 ± 5.65, p<0.001), mean PQ interval change at 1 (0.01 ± 0.031 and 0.02 ± 0.022, p=0.003) and 6 months (0.01 ± 0.032 and 0.02 ± 0.024, p=0.003). The risk of adverse drug reactions was higher in patients with the CYP2D6*10 CT genotype compared with CC: mean HR change at 1 month (2.94 ± 4.65 and 6.34 ± 5.66, p<0.001) and 6 months (5.20 ± 8.90 and 7.78 ± 5.75, p<0.001), mean PQ interval change at 1 (0.01 ± 0.032 and 0.02 ± 0.021, p=0.014) and 6 months (0.01 ± 0.033 and 0.02 ± 0.022, p=0.014).

CONCLUSIONS: CYP2D6*4 and CYP2D6*10 gene polymorphisms may affect a higher risk of timolol-induced bradycardia and increased PQ interval of treatment medications containing 0.5% of timolol maleate in patients with POAG.

PMID:36001461 | DOI:10.1515/dmpt-2022-0117

Curr Treat Options Oncol. 2022 Aug 24. doi: 10.1007/s11864-022-01010-x. Online ahead of print.

ABSTRACT

Pharmacogenomics is increasingly important to guide objective, safe, and effective individualised prescribing. Personalised prescribing has revolutionised treatments in the past decade, allowing clinicians to maximise drug efficacy and minimise adverse effects based on a person's genetic profile. Opioids, the gold standard for cancer pain relief, are among the commonest medications prescribed in palliative care practice. This narrative review examines the literature surrounding opioid pharmacogenomics and its applicability to the palliative care cancer population. There is currently limited intersection between the fields of palliative care and pharmacogenomics, but growing evidence presents a need to build linkages between the two disciplines. Pharmacogenomic evidence guiding opioid prescribing is currently available for codeine and tramadol, which relates to CYP2D6 gene variants. However, these medications are prescribed less commonly for pain in palliative care. Research is accelerating with other opioids, where oxycodone (CYP2D6) and methadone (CYP2B6, ABCB1) already have moderate evidence of an association in terms of drug metabolism and downstream analgesic response and side effects. OPRM1 and COMT are receiving increasing attention and have implications for all opioids, with changes in opioid dosage requirements observed but they have not yet been studied widely enough to be considered clinically actionable. Current evidence indicates that incorporation of pharmacogenomic testing into opioid prescribing practice should focus on the CYP2D6 gene and its actionable variants. Although opioid pharmacogenomic tests are not widely used in clinical practice, the progressively reducing costs and rapid turnover means greater accessibility and affordability to patients, and thus, clinicians will be increasingly asked to provide guidance in this area. The upsurge in pharmacogenomic research will likely discover more actionable gene variants to expand international guidelines to impact opioid prescribing. This rapidly expanding area requires consideration and monitoring by clinicians in order for key findings with clinical implications to be accessible, meaningfully interpretable and communicated.

PMID:36001223 | DOI:10.1007/s11864-022-01010-x

Pharmacogenomics. 2022 Aug 24. doi: 10.2217/pgs-2022-0064. Online ahead of print.

ABSTRACT

Pharmacogenetics is the relationship between an individual's genetic variations and their response to pharmacological treatment. We conducted an overview of reviews on the use of post-treatment pharmacogenetic testing for oncology, based on clinically relevant gene-drug pairs. We conducted a search on Medline, Embase and Cochrane Library, from their inception to 18 June 2020. We selected six eligible systematic reviews. The most studied drug categories were estrogen agonists/antagonists and fluoropyrimidines associated with cytochrome P450 and dihydropyrimidine dehydrogenase genes (CYP2D6 and DPYD), but many studies were classified as being of critically low or low quality. There is a need for more high-quality primary studies and systematic reviews that assess the risk of bias, with consistent definitions of clinical outcomes to consider the benefits of pharmacogenetic testing for oncology.

PMID:36001087 | DOI:10.2217/pgs-2022-0064

Pediatr Dermatol. 2022 Jul;39(4):601-605. doi: 10.1111/pde.15074.

ABSTRACT

Toxic epidermal necrolysis (TEN) is a rare and acute life-threatening condition and one of the severe cutaneous adverse drug reactions. There are limited data on TEN from the COVID-19 vaccine regarding its pathogenesis, treatment, and prognosis, particularly in children. We report a case of COVID-19 vaccine-induced TEN and the patient's human leukocyte antigen pharmacogenomic profile.

PMID:36000937 | DOI:10.1111/pde.15074

Pediatr Dermatol. 2022 Jul;39(4):671-672. doi: 10.1111/pde.14987.

NO ABSTRACT

PMID:36000935 | DOI:10.1111/pde.14987

Health Sci Rep. 2022 Aug 18;5(5):e789. doi: 10.1002/hsr2.789. eCollection 2022 Sep.

ABSTRACT

COVID-19 is not only limited to a defined array but also has expanded with several secondary infections. Two uncommon opportunistic fungal infections, COVID-19 associated mucormycosis (CAM) and aspergillosis (CAA), have recently been highly acquainted by many worldwide cases. Two immune response deteriorating factors are considered to be responsible for immunosuppression: comorbidities and medication. Due to unlike infection sites and patterns, CAM and CAA-associated factors deflect a few degrees of proximity, and the present study is for its assessment. The study evaluated 351 CAM cases and 191 CAA cases retrieved from 65 and 53 articles based on inclusion criteria, respectively. Most of the CAM reported from India and CAA were from four South-European and West-European neighbor countries. The mean ages of CAM and CAA were 52.72 ± 13.74 and 64.81 ± 11.14, correspondingly. Mortality of CAA (56.28%) was two times greater than CAM (26.02%). Nevertheless, the count of diabetes cases was very high in CAM compared to CAA. The main comorbidities of CAM were diabetes (nearly 80%) and hypertension (more than 38%). All noticeable complications were higher in CAA except diabetes, and these were diabetes (34.55%), hypertension (45.03%), and obesity (18.32%). Moreover, pre-existing respiratory complications like asthma and chronic obstructive pulmonary disease are visible in CAA. The uses of steroids in CAM and CAA were nearly 70% and 66%, respectively. Almost one-fourth of CAA cases were reported using immunosuppressant monoclonal antibodies, whereas only 7.69% were for CAM. The overall finding highlights diabetes, hypertension, and steroids as the risk factors for CAM, whereas obesity, chronic pulmonary disease, and immunosuppressants for CAA.

PMID:36000078 | PMC:PMC9387898 | DOI:10.1002/hsr2.789

Mol Cancer. 2022 Aug 23;21(1):169. doi: 10.1186/s12943-022-01631-8.

ABSTRACT

BACKGROUND: Genetic variants associated with acute side effects of radiotherapy in nasopharyngeal carcinoma (NPC) remain largely unknown.

METHODS: We performed a two-stage genome-wide association analysis including a total of 1084 patients, where 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant variants were then validated in an independent cohort of 765 patients using the MassARRAY system. Gene mapping, linkage disequilibrium, genome-wide association analysis, and polygenic risk score were conducted or calculated using FUMA, LDBlockShow, PLINK, and PRSice software programs, respectively.

RESULTS: Five SNPs (rs6711678, rs4848597, rs4848598, rs2091255, and rs584547) showed statistical significance after validation. Radiotherapy toxicity was more serious in mutant minor allele carriers of all five SNPs. Stratified analysis further indicated that rs6711678, rs4848597, rs4848598, and rs2091255 correlated with skin toxicity in patients of EBV positive, late stage (III and IV), receiving both concurrent chemoradiotherapy and induction/adjuvant chemotherapy, and with OR values ranging from 1.92 to 2.66. For rs584547, high occurrence of dysphagia was found in A allele carriers in both the discovery (P = 1.27 × 10- 6, OR = 1.55) and validation (P = 0.002, OR = 4.20) cohorts. Furthermore, prediction models integrating both genetic and clinical factors for skin reaction and dysphagia were established. The area under curve (AUC) value of receiver operating characteristic (ROC) curves were 0.657 (skin reaction) and 0.788 (dysphagia).

CONCLUSIONS: Rs6711678, rs4848597, rs4848598, and rs2091255 on chromosome 2q14.2 and rs584547 were found to be novel risk loci for skin toxicity and dysphagia in NPC patients receiving radiotherapy.

TRIAL REGISTRATION: Chinese Clinical Trial Register (registration number: ChiCTR-OPC-14005257 and CTXY-140007-2).

PMID:35999636 | DOI:10.1186/s12943-022-01631-8

Am J Hypertens. 2022 Aug 24:hpac098. doi: 10.1093/ajh/hpac098. Online ahead of print.

ABSTRACT

BACKGROUND: In the United States, hypertension disproportionately afflicts over half of African American adults, many of whom also experience racial discrimination. Understanding gene x discrimination effects may help explain racial disparities in hypertension.

METHODS: We tested for main effects and interactive effects of five candidate single nucleotide polymorphisms (SNPs: rs2116737, rs11190458, rs2445762, rs2597955, rs2416545) and experiences of discrimination on blood pressure (BP) in African Americans not taking antihypertensive medications in the Jackson Heart Study from Mississippi (n=2933). Multiple linear regression models assumed an additive genetic model and adjusted for ancestry, age, sex, body mass index, education, and relatedness. We additionally tested recessive and dominant genetic models.

RESULTS: Discrimination was significantly associated with higher diastolic BP (p=0.003). In contrast, there were no main effects of any SNP on BP. When analyzing SNPs and discrimination together, SGCD (Sarcoglycan Delta; rs2116737) demonstrated a gene x environment interaction. Specifically, a SGCD x Discrimination interaction was associated with systolic BP (β=1.95, p=0.00028) in a recessive model. Participants carrying a T allele, regardless of discrimination experiences, and participants with a GG genotype and high experiences of discrimination had higher systolic BP than participants with a GG genotype and low experiences of discrimination. This finding suggests the SGCD GG genotype may have a protective effect on systolic BP, but only in a setting of low discrimination.

CONCLUSIONS: The inclusion of culturally relevant stressors, like discrimination, may be important to understand the gene-environment interplay likely underlying complex diseases with racial health inequities.

PMID:35999027 | DOI:10.1093/ajh/hpac098

Brief Bioinform. 2022 Aug 23:bbac338. doi: 10.1093/bib/bbac338. Online ahead of print.

ABSTRACT

As a frontier field of individualized therapy, microRNA (miRNA) pharmacogenomics facilitates the understanding of different individual responses to certain drugs and provides a reasonable reference for clinical treatment. However, the known drug resistance-associated miRNAs are not yet sufficient to support precision medicine. Although existing methods are effective, they all focus on modelling miRNA-drug resistance interaction graphs, making their performance bounded by the interaction density. In this study, we propose a framework for miRNA-drug resistance prediction through efficient neural architecture search and graph isomorphism networks (NASMDR). NASMDR uses attribute information instead of the commonly used interactive graph information. In the cross-validation experiment, the proposed framework can achieve an AUC of 0.9468 on the ncDR dataset, which is 2.29% higher than the state-of-the-art method. In addition, we propose a novel sequence characterization approach, k-mer Sparse Nonnegative Matrix Factorization (KSNMF). The results show that NASMDR provides novel insights for integrating efficient neural architecture search and graph isomorphic networks into a unified framework to predict drug resistance-related miRNAs. The codes for NASMDR are available at https://github.com/kaizheng-academic/NASMDR.

PMID:35998922 | DOI:10.1093/bib/bbac338

Biochem Pharmacol. 2022 Aug 20:115225. doi: 10.1016/j.bcp.2022.115225. Online ahead of print.

ABSTRACT

Hepatocellular carcinoma (HCC) arises principally against a background of cirrhosis and these two diseases are responsible globally for over 2 million deaths a year. There are few treatment options for liver cirrhosis and HCC, so it is vital to arrest these pathologies early in their development. To do so, we propose dietary and therapeutic solutions that involve the gut microbiota and its consequences. Integrated dietary, environmental and intrinsic signals result in a bidirectional connection between the liver and the gut with its microbiota, known as the gut-liver axis. Numerous lifestyle factors can result in dysbiosis with a change in the functional composition and metabolic activity of the microbiota. A panoply of metabolites can be produced by the microbiota, including ethanol, secondary bile acids, trimethylamine, indole, quinolone, phenazine and their derivatives and the quorum sensor acyl homoserine lactones that may contribute to HCC but have yet to be fully investigated. Gram-negative bacteria can activate the pattern recognition receptor toll-like receptor 4 (TLR4) in the liver leading to nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, which can contribute to HCC initiation and progression. The goal in preventing HCC should be to ensure a healthy gut microbiota using probiotic supplements containing beneficial bacteria and prebiotic plant fibers such as oligosaccharides that stimulate their growth. The clinical development of TLR4 antagonists is urgently needed to counteract the pathological effects of dysbiosis on the liver and other organs. Further nutrigenomic studies are required to understand better how the diet influences the gut microbiota and its adverse effects on the liver.

PMID:35998677 | DOI:10.1016/j.bcp.2022.115225

Public Health Genomics. 2022 Aug 23:1-9. doi: 10.1159/000525684. Online ahead of print.

ABSTRACT

INTRODUCTION: Precision medicine research investigates the differences in individuals' genetics, environment, and lifestyle to tailor health prevention and treatment options as part of an emerging model of health care delivery. Advancing precision medicine research will require effective communication across a wide range of scientific and health care disciplines and with research participants who represent diverse segments of the population.

METHODS: A multidisciplinary group convened over the course of a year and developed precision medicine research case examples to facilitate precision medicine research discussions with communities.

RESULTS: A shared definition of precision medicine research as well as six case examples of precision medicine research involving genetic risk, pharmacogenetics, epigenetics, the microbiome, mobile health, and electronic health records were developed.

DISCUSSION/CONCLUSION: The precision medicine research definition and case examples can be used as planning tools to establish a shared understanding of the scope of precision medicine research across multidisciplinary teams and with the diverse communities in which precision medicine research will take place. This shared understanding is vital for successful and equitable progress in precision medicine.

PMID:35998578 | DOI:10.1159/000525684

Expert Opin Drug Metab Toxicol. 2022 Aug 23. doi: 10.1080/17425255.2022.2114344. Online ahead of print.

ABSTRACT

INTRODUCTION: Cytochrome P450s (CYPs) are a superfamily of monooxygenases with diverse biological roles. CYP2J2 is an isozyme highly expressed in the heart where it metabolizes endogenous substrates such as N-3/N-6 polyunsaturated fatty acids (PUFA) to produce lipid mediators involved in homeostasis and cardioprotective responses. Expanding our knowledge of the role CYP2J2 has within the heart is important for understanding its impact on cardiac health and disease.

AREAS COVERED: The objective of this review was to assess the state of knowledge regarding cardiac CYP2J2. A literature search was conducted using PubMed-MEDLINE (from 2022 and earlier) to evaluate relevant studies regarding CYP2J2 mediated cardioprotection, small molecule modulators, effects of CYP2J2 substrates toward biologically relevant effects and implications of CYP2J2 polymorphisms and sexual dimorphism in the heart.

EXPERT OPINION: Cardiac CYP2J2-mediated metabolism of endogenous and exogenous substrates have been shown to impact cardiac function. Identifying individual factors, like sex and age, that affect CYP2J2 require further elucidation to better understand CYP2J2's clinical relevance. Resolving the biological targets and activities of CYP2J2-derived PUFA metabolites will be necessary to safely target CYP2J2 and design novel analogues. Targeting CYP2J2 for therapeutic aims offers a potential novel approach to regulating cardiac homeostasis, drug metabolism and cardioprotection.

PMID:35997132 | DOI:10.1080/17425255.2022.2114344

MicroPubl Biol. 2022 Aug 4;2022. doi: 10.17912/micropub.biology.000618. eCollection 2022.

ABSTRACT

Apart from the highly conserved role in the cellular degradation process, autophagy also appears to play a key role in cellular proliferation. Here, we describe the genetic interaction of autophagy-related genes and Pmk1 MAPK signaling in fission yeast. atg1 deletion cells (Δ atg1 ) exhibit the vic (viable in the presence of immunosuppressant and Cl - ) phenotype, indicative of Pmk1 signaling inhibition. Moreover, the Δ atg1 Δ pmk1 double mutant resembles the single Δ pmk1 mutant, suggesting that Atg1 functions in the Pmk1 pathway. In addition, the growth defect induced by overexpression of Pck2, an upstream activator of Pmk1 MAPK was alleviated by the deletion of atg1 + . Finally, the deletion of autophagy-related genes recapitulates Pmk1 MAPK signaling inhibition. Our data suggest a novel role for autophagy in MAPK signaling regulation.

PMID:35996690 | PMC:PMC9391948 | DOI:10.17912/micropub.biology.000618

Pharmacol Ther. 2022 Aug 19:108268. doi: 10.1016/j.pharmthera.2022.108268. Online ahead of print.

ABSTRACT

Organic cation transporters (OCT), organic anion transporting polypeptides (OATP) and organic anion transporters (OAT) from the solute carrier (SLC) family play an essential role in the uptake of endogenous compounds and drugs into the hepatocytes and other cell types. The well-documented interindividual variability of expression and activity of these transporters translates into interindividual variability in drug pharmacokinetics and drug response. It is therefore important to elucidate mechanisms affecting membrane transporter expression and function. These mechanisms include transcriptional regulation, disease-dependent regulation and genetic variation. In this review, we will summarize the current knowledge of the molecular functions and substrate profiles of cloned hepatic OCTs, OATPs and OATs and discuss recent advances in understanding variable expression and function. Finally, the role of genetic variation in these transporters on drug exposure will be presented with implications for individual drug response.

PMID:35995278 | DOI:10.1016/j.pharmthera.2022.108268