Decreased MMP1 gene expression in acute myeloid leukaemia.

Mol Biol Rep. 2019 Apr;46(2):2293-2298

Authors: Pietrzak J, Mirowski M, Jeleń A, Świechowski R, Wodziński D, Niebudek K, Balcerczak E

Abstract
Acute myeloid leukaemia (AML) is a heterogeneous disorder of haematopoietic stem cells or progenitor cells. Metalloproteinases (MMPs) are proteolytic enzymes whose activity is increased in different types of solid tumours. These enzymes regulate many processes associated with tumour progression. In haematological malignancy, the role of MMPs seems to be underestimated, and only metalloproteinase 2 (MMP2) and metalloproteinase 9 (MMP9) have been widely examined so far. In this work, differences in metalloproteinase 1 (MMP1) gene expression between patients with AML and healthy individuals were assessed. The relative expression level of the MMP1 gene was obtained by a real time PCR method preceded by reverse transcription. The relative level of MMP1 gene expression in patients with AML was decreased when compared to that of the control group. The role of MMP1 in AML could be different from that in solid tumours. Decreased MMP1 gene expression in AML similar to that of MMP9, shows a greater role for MMP1 in normal haematopoiesis than in the development of leukaemic cells.

PMID: 30747385 [PubMed - indexed for MEDLINE]

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Relationship between ABCC4 SNPs and hepatitis B virus suppression during tenofovir-containing antiretroviral therapy in patients with HIV/HBV coinfection.

J Acquir Immune Defic Syndr. 2019 Jul 03;:

Authors: Archampong T, Ojewale O, Bears K, Chen Y, Lartey M, Sagoe KW, Obo-Akwa A, Gong Y, Langaee T, Kwara A

Abstract
BACKGROUND: Incomplete hepatitis B virus (HBV) suppression during antiretroviral therapy (ART) in human immunodeficiency virus (HIV) and HBV co-infected patients is common, but underlying factors are not fully elucidated. We hypothesize that genetic factors that influence nucleoside analog pharmacokinetics will affect HBV treatment response.
METHODS: HIV/HBV co-infected patients on tenofovir disoproxil fumarate/lamivudine ((TDF/3TC)-containing ART were enrolled. Selected ABCC4 single nucleotide polymorphisms (SNPs) with known effects on nucleoside pharmacokinetics were genotyped using TaqMan® assays. Relationship between ABCC4 SNPs and unsuppressed HBV DNA (HBV DNA ≥ 20 IU/mL) were examined.
RESULTS: Of the 50 participants on TDF/3TC-containing ART for a median (range) of 1.5 (1 to 7.4) years, 20 (40%) had unsuppressed HBV DNA. Participants with unsuppressed compared to those with suppressed HBV DNA were more likely to have negative HBe antibody, lower body mass index (BMI) and lower CD4 count at enrolment. Carriers of ABCC4 rs11568695 (G3724A) variant allele were more likely than non-carriers to have unsuppressed HBV (61.1% vs. 29.0%, P = 0.038). Among 36 patients with suppressed HIV RNA (presumed good ART adherence), ABCC4 rs11568695 variant carriers were more likely than non-carriers to have unsuppressed HBV (58.8% vs. 20.0% P=0.021). Logistic regression analysis that included genetic and non-genetic factors identified ABCC4 rs11568695 variant allele, BMI and male sex as predictors of unsuppressed HBV DNA.
CONCLUSION: We identified a novel association between ABCC4 rs11568695 SNP and poor HBV treatment response. If confirmed in further studies, ABCC4 genotyping could be used to identify individuals who may need intensified HBV therapy.

PMID: 31335591 [PubMed - as supplied by publisher]

Inactivation of Prostaglandin E2 as a Mechanism for UGT2B17-Mediated Adverse Effects in Chronic Lymphocytic Leukemia.

Front Oncol. 2019;9:606

Authors: Allain EP, Rouleau M, Le T, Vanura K, Villeneuve L, Caron P, Turcotte V, Lévesque E, Guillemette C

Abstract
High expression of the metabolic enzyme UDP-glucuronosyltransferase UGT2B17 in chronic lymphocytic leukemia (CLL) cells was associated with poor prognosis in two independent studies. However, the underlying mechanism remains unknown. We hypothesized that UGT2B17 impacts intracellular levels of hormone-like signaling molecules involved in the regulation of gene expression in leukemic cells. We initially confirmed in a third cohort of 291 CLL patients that those with high UGT2B17 displayed poor prognosis (hazard ratio of 2.31, P = 0.015). Consistent with the unfavorable prognostic significance of elevated UGT2B17 expression in CLL patients, high UGT2B17 expression was associated with enhanced proliferation of MEC1 and JVM2 malignant B-cell models. Transcriptomic analyses revealed that high UGT2B17 was linked to a significant alteration of genes related to prostaglandin E2 (PGE2) and to its precursor arachidonic acid, both in cell models and a cohort of 448 CLL patients. In functional assays, PGE2 emerged as a negative regulator of apoptosis in CLL patients and proliferation in cells models, whereas its effect was partially abrogated by high UGT2B17 expression in MEC1 and JVM2 cells. Enzymatic assays and mass-spectrometry analyses established that the UGT2B17 enzyme inactivates PGE2 by its conjugation to glucuronic acid (GlcA) leading to the formation of two glucuronide (G) derivatives. High UGT2B17 expression was further associated with a proficient inactivation of PGE2 to PGE2-G in CLL patient cells and cell models. We conclude that UGT2B17-dependent PGE2 glucuronidation impairs anti-oncogenic PGE2 effects in leukemic cells, thereby partially contributing to disease progression in high UGT2B17 CLL patients.

PMID: 31334126 [PubMed]

N-acetyltransferase 2 polymorphism and acetylation profiles in Buginese ethnics of Indonesia.

Ann Hum Genet. 2019 Jul 22;:

Authors: Yuliwulandari R, Susilowati RW, Razari I, Viyati K, Umniyati H, Prayuni K

Abstract
BACKGROUND: N-acetyltransferase 2 (NAT2) is a key enzyme involved in the phase II metabolism of aromatic amines and heterocyclic aromatic amines present in a wide range of xenobiotics. The aim of this study was to investigate the NAT2 polymorphism in the Buginese ethnic group of Indonesia to determine the frequency of NAT2 alleles in this population.
RESULTS: We found six haplotypes consisting of six single-nucleotide polymorphisms and 12 NAT2 genotype variations. NAT2*6A haplotype (42%) showed the highest frequency, followed by NAT2*4 (33%), NAT2*7B (15%), NAT2*5B (5%), NAT2*12A (3%), and NAT2*13 (2%). In terms of phenotypes, the Buginese population comprised 18% rapid acetylators, 40% intermediate acetylators, and 42% slow acetylators.
CONCLUSION: We confirmed the high-frequency slow acetylator phenotype in the Buginese population. The NAT2*6A/*6A genotype was the most frequent slow acetylator genotype, followed by NAT2*6A/*7B. The pattern of NAT2 alleles of Buginese is similar to Southeast Asian populations but not Northeast Asian populations. However, the slow acetylator frequencies in the Buginese population were higher than those in Northeast Asian populations and lower than those in Caucasians and some American populations.

PMID: 31332782 [PubMed - as supplied by publisher]

Effect of first-line antituberculosis therapy on nevirapine pharmacokinetics in children younger than 3 years old.

Antimicrob Agents Chemother. 2019 Jul 22;:

Authors: Enimil A, Antwi S, Yang H, Dompreh A, Alghamdi WA, Gillani FS, Orstin A, Bosomtwe D, Opoku T, Norman J, Wiesner L, Langaee T, Peloquin CA, Court MH, Greenblatt DJ, Kwara A

Abstract
Nevirapine-based antiretroviral therapy is one of the limited options in HIV-infected children younger than 3 years old (young children) with tuberculosis (TB) coinfection. To date, there is insufficient data to recommend nevirapine-based therapy during first-line antituberculosis (anti-TB) therapy in young children. We compared nevirapine pharmacokinetics (PK) in HIV-infected young children with and without TB coinfection. In the co-infected group, nevirapine PK was evaluated while on anti-TB therapy and after completing anti-TB therapy regimen. Of 53 participants, 23 (43%) had TB/HIV coinfection. While the mean difference in nevirapine PK parameters between the two groups was not significant (P > 0.05), 14/23 (61%) of children with TB/HIV coinfection and 9/29 (31%) with HIV infection had nevirapine minimum concentration (Cmin) below the proposed target of 3.0 mg/L (P = 0.03). In multivariate analysis, anti-TB therapy and CYP2B6 516G>T genotype were joint predictors of nevirapine PK parameters. Differences in nevirapine PK parameters between the two groups were significant in children with CYP2B6 516GG but not GT or TT genotypes. Among 14 TB/HIV co-infected participants with paired data, the geometric mean Cmin and AUC0-12h were about 34% lower when patients were taking anti-TB therapy, while the nevirapine apparent oral clearance (CL/F) was about 45% higher. While the induction effect of anti-TB therapy on nevirapine PK in our study was modest, the CYP2B6 genotype-dependent variability in TB drugs effect would complicate any dose-adjustment strategy in young children with TB/HIV coinfection. Alternate ART-regimens that are more compatible with TB treatment in this age group is needed.

PMID: 31332062 [PubMed - as supplied by publisher]

Age-Dependent Levels of Protein Kinase Cs in Brain: Reduction of Endogenous Mechanisms of Neuroprotection.

Int J Mol Sci. 2019 Jul 19;20(14):

Authors: Pastore D, Pacifici F, Dave KR, Palmirotta R, Bellia A, Pasquantonio G, Guadagni F, Donadel G, Di Daniele N, Abete P, Lauro D, Rundek T, Perez-Pinzon MA, Della-Morte D

Abstract
Neurodegenerative diseases are among the leading causes of mortality and disability worldwide. However, current therapeutic approaches have failed to reach significant results in their prevention and cure. Protein Kinase Cs (PKCs) are kinases involved in the pathophysiology of neurodegenerative diseases, such as Alzheimer's Disease (AD) and cerebral ischemia. Specifically ε, δ, and γPKC are associated with the endogenous mechanism of protection referred to as ischemic preconditioning (IPC). Existing modulators of PKCs, in particular of εPKC, such as ψεReceptor for Activated C-Kinase (ψεRACK) and Resveratrol, have been proposed as a potential therapeutic strategy for cerebrovascular and cognitive diseases. PKCs change in expression during aging, which likely suggests their association with IPC-induced reduction against ischemia and increase of neuronal loss occurring in senescent brain. This review describes the link between PKCs and cerebrovascular and cognitive disorders, and proposes PKCs modulators as innovative candidates for their treatment. We report original data showing εPKC reduction in levels and activity in the hippocampus of old compared to young rats and a reduction in the levels of δPKC and γPKC in old hippocampus, without a change in their activity. These data, integrated with other findings discussed in this review, demonstrate that PKCs modulators may have potential to restore age-related reduction of endogenous mechanisms of protection against neurodegeneration.

PMID: 31331067 [PubMed - in process]

Pendant HDAC inhibitor SAHA derivatised polymer as a novel prodrug micellar carrier for anticancer drugs.

J Drug Target. 2018 Jun - Jul;26(5-6):448-457

Authors: Xu J, Sun J, Wang P, Ma X, Li S

Abstract
Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDACi) approved by FDA for the treatment of cutaneous T cell lymphoma, is a promising anticancer drug for various cancers with a unique mode of action. However, it demonstrates limited clinical benefits in solid tumours as a single drug. In order to achieve enhanced and synergistic co-delivery of SAHA and doxorubicin (DOX), a cleavable SAHA-based prodrug polymer (POEG-b-PSAHA), consisting of hydrophilic poly(oligo(ethylene glycol) methacrylate) (POEG) blocks and hydrophobic SAHA segments, has been developed. POEG-b-PSAHA prodrug polymer was able to form spherical micelles with a diameter around 60 nm and well retained the pharmacological activity of SAHA in either inhibiting the proliferation of tumour cells or inducing histone acetylation. DOX formulated in POEG-b-PSAHA-based micelles showed a sustained release profile. DOX-loaded POEG-b-PSAHA exhibited more potent cytotoxicity towards tumour cells than free DOX and DOX loaded in a pharmacologically 'inert' nanocarrier, POEG-b-POM. Consistently, DOX/POEG-b-PSAHA formulation resulted in an improved therapeutic effect in vivo compared to free DOX, Doxil or DOX formulated in POEG-b-POM micelles. These results suggest that SAHA-based prodrug micelles may serve as a dual functional carrier for combination strategies in epigenetic-oriented anticancer therapy.

PMID: 29251528 [PubMed - indexed for MEDLINE]

Structured override reasons for drug-drug interaction alerts in electronic health records.

J Am Med Inform Assoc. 2019 Apr 26;:

Authors: Wright A, McEvoy DS, Aaron S, McCoy AB, Amato MG, Kim H, Ai A, Cimino JJ, Desai BR, El-Kareh R, Galanter W, Longhurst CA, Malhotra S, Radecki RP, Samal L, Schreiber R, Shelov E, Sirajuddin AM, Sittig DF

Abstract
OBJECTIVE: The study sought to determine availability and use of structured override reasons for drug-drug interaction (DDI) alerts in electronic health records.
MATERIALS AND METHODS: We collected data on DDI alerts and override reasons from 10 clinical sites across the United States using a variety of electronic health records. We used a multistage iterative card sort method to categorize the override reasons from all sites and identified best practices.
RESULTS: Our methodology established 177 unique override reasons across the 10 sites. The number of coded override reasons at each site ranged from 3 to 100. Many sites offered override reasons not relevant to DDIs. Twelve categories of override reasons were identified. Three categories accounted for 78% of all overrides: "will monitor or take precautions," "not clinically significant," and "benefit outweighs risk."
DISCUSSION: We found wide variability in override reasons between sites and many opportunities to improve alerts. Some override reasons were irrelevant to DDIs. Many override reasons attested to a future action (eg, decreasing a dose or ordering monitoring tests), which requires an additional step after the alert is overridden, unless the alert is made actionable. Some override reasons deferred to another party, although override reasons often are not visible to other users. Many override reasons stated that the alert was inaccurate, suggesting that specificity of alerts could be improved.
CONCLUSIONS: Organizations should improve the options available to providers who choose to override DDI alerts. DDI alerting systems should be actionable and alerts should be tailored to the patient and drug pairs.

PMID: 31329891 [PubMed - as supplied by publisher]

Ready or not, here it comes: Direct-to-consumer pharmacogenomic testing and its implications for community pharmacists.

J Am Pharm Assoc (2003). 2019 Jul 18;:

Authors: Gammal RS, Mayes J, Caudle KE

Abstract
OBJECTIVE: To explore the implications of direct-to-consumer pharmacogenomic testing for community pharmacy practice.
SUMMARY: In October 2018, the U.S. Food and Drug Administration provided approval for direct-to-consumer genetic testing company, 23andMe (Mountain View, CA), to return select pharmacogenomic test results to their customers. Given the community pharmacist's high accessibility to the public and in-depth knowledge of pharmacology, and the availability of direct-to-consumer genetic testing kits at pharmacies, it is likely that patients will present their pharmacogenomic test results to their pharmacists and expect them to incorporate those results into their care. It is important, therefore, that community pharmacists are aware of the clinical implications of these results, know where to turn for evidence-based clinical pharmacogenomics information, and be mindful of the need for confirmatory testing before changing therapy.
CONCLUSION: Community pharmacists are at the frontlines of health care, and as such will be at the frontlines of direct-to-consumer pharmacogenomic testing. In the near future, it is likely that community pharmacists will need to counsel patients on the interpretation and appropriate use of direct-to-consumer pharmacogenomic test results.

PMID: 31327749 [PubMed - as supplied by publisher]

Gene Variants at Loci Related to Blood Pressure Account for Variation in Response to Antihypertensive Drugs Between Black and White Individuals.

Hypertension. 2019 Jul 22;:HYPERTENSIONAHA11812177

Authors: Iniesta R, Campbell D, Venturini C, Faconti L, Singh S, Irvin MR, Cooper-DeHoff RM, Johnson JA, Turner ST, Arnett DK, Weale ME, Warren H, Munroe PB, Cruickshank K, Padmanabhan S, Lewis C, Chowienczyk P

Abstract
Selection of antihypertensive treatment according to self-defined ethnicity is recommended by some guidelines but might be better guided by individual genotype rather than ethnicity or race. We compared the extent to which variation in blood pressure response across different ethnicities may be explained by genetic factors: genetically defined ancestry and gene variants at loci known to be associated with blood pressure. We analyzed data from 5 trials in which genotyping had been performed (n=4696) and in which treatment responses to β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blocker, thiazide or thiazide-like diuretic and calcium channel blocker were available. Genetically defined ancestry for proportion of African ancestry was computed using the 1000 genomes population database as a reference. Differences in response to the thiazide diuretic hydrochlorothiazide, the β-blockers atenolol and metoprolol, the angiotensin-converting enzyme inhibitor lisinopril, and the angiotensin receptor blocker candesartan were more closely associated to genetically defined ancestry than self-defined ethnicity in admixed subjects. A relatively small number of gene variants related to loci associated with drug-signaling pathways (KCNK3, SULT1C3, AMH, PDE3A, PLCE1, PRKAG2) with large effect size (-3.5 to +3.5 mm Hg difference in response per allele) and differing allele frequencies in black versus white individuals explained a large proportion of the difference in response to candesartan and hydrochlorothiazide between these groups. These findings suggest that a genomic precision medicine approach can be used to individualize antihypertensive treatment within and across populations without recourse to surrogates of genetic structure such as self-defined ethnicity.

PMID: 31327267 [PubMed - as supplied by publisher]

[Tacrolimus therapy after renal transplantation. Current questions of concentration/dose ratio].

Orv Hetil. 2019 Jul;160(30):1178-1183

Authors: Varga Á, Kalmár Nagy K, Szakály P

Abstract
Tacrolimus is an important part of immunosuppressive therapy after solid organ transplantation. The therapeutic range of the drug from the calcineurin inhibitor group is narrow. Adjustment of the blood concentration can be very complicated but to be able to avoid the occurrence of side effects or ineffective immunosuppression it is inevitable. This article summarizes the properties of tacrolimus pharmacokinetics, pharmacogenetics and pharmacodynamics. We will focus on individual variations of cytochrome enzymes. In the following part, a new method for screening high risk patients will be introduced. We will present the publications of the determination of the concentration/dose (C/D) ratio. By determining the C/D ratio, researchers identify fast and slow metabolizing patient groups. Fast metabolizers require higher doses in general and the occurrence of complications is also more frequent in this group. Long-term results are lagging behind the slow metabolizing group. The long-term results of renal transplantation nowadays contribute to the postoperative period and the later years rather than the surgery itself. It includes the proper management of previous illnesses (e.g., hypertension, diabetes, endocrinological problems), detection of complications (e.g., infections, malignancies), and the precise regulation of immunosuppressive therapy. Orv Hetil. 2019; 160(30): 1178-1183.

PMID: 31327249 [PubMed - in process]

Precision medicine in the management of type 2 diabetes.

Lancet Diabetes Endocrinol. 2018 11;6(11):891-900

Authors: Gloyn AL, Drucker DJ

Abstract
The study of type 2 diabetes has been driven by advances in human genetics, epigenetics, biomarkers, mechanistic studies, and large clinical trials, enabling new insights into disease susceptibility, pathophysiology, progression, and development of complications. Simultaneously, several new drug classes with different mechanisms of action have been introduced over the past two decades, accompanied by data about cardiovascular safety and non-glycaemic outcomes. In this Review, we critically examine the progress and integration of this new science into clinical practice, and review opportunities for enabling the use of precision medicine in the diagnosis and treatment of type 2 diabetes. We contrast the success in delivering personalised medicine for monogenic diabetes with the greater challenge of providing a precision medicine approach for type 2 diabetes, highlighting gaps, limitations, and areas requiring further study.

PMID: 29699867 [PubMed - indexed for MEDLINE]

Developmental low-dose exposure to bisphenol A induces chronic inflammation, bone marrow fibrosis and reduces bone stiffness in female rat offspring only.

Environ Res. 2019 Jul 11;177:108584

Authors: Lind T, Lejonklou MH, Dunder L, Kushnir MM, Öhman-Mägi C, Larsson S, Melhus H, Lind PM

Abstract
BACKGROUND: Developmental exposure to low doses of the endocrine disruptor bisphenol A (BPA) is known to alter bone tissue in young rodents, although how bone tissue is affected in aged animals is not well known. We have recently shown that low-dose developmental exposure to BPA increases procollagen type I N-terminal propeptide (P1NP) levels, a peptide formed during type 1 collagen synthesis, in plasma of 5-week-old female rat offspring while male offspring showed reduced bone size.
OBJECTIVE: To analyze offspring bone phenotype at 52 weeks of age and clarify whether the BPA-induced increase in P1NP levels at 5 weeks is an early sign of bone marrow fibrosis development.
METHODS: As in our 5-week study, pregnant Fischer 344 rats were exposed to BPA via drinking water corresponding to 0.5 μg/kg BW/day (BPA0.5), which is in the range of human daily exposure, or 50 μg/kg BW/day (BPA50) from gestational day 3.5 until postnatal day 22. Controls were given only vehicle. The offspring were sacrificed at 52 weeks of age. Bone effects were analyzed using peripheral quantitative and micro-computed tomography (microCT), 3-point bending test, plasma markers and histological examination.
RESULTS: Compared to a smaller bone size at 5 weeks, at the age of 52 weeks, femur size in male offspring had been normalized in developmentally BPA-exposed rats. The 52-week-old female offspring showed, like the 5-week-old siblings, higher plasma P1NP levels compared to controls but no general increasing bone growth or strength. However, 2 out of 14 BPA-exposed female offspring bones developed extremely thick cortices later in life, discovered by systematic in vivo microCT scanning during the study. This was not observed in male offspring or in female controls. Biomechanical testing revealed that both doses of developmental BPA exposure reduced femur stiffness only in female offspring. In addition, histological analysis showed an increased number of fibrotic lesions only in the bone marrow of female rat offspring developmentally exposed to BPA. In line with this, plasma markers of inflammation, Tnf (in BPA0.5) and Timp1 (in BPA50) were increased exclusively in female offspring.
CONCLUSIONS: Developmental BPA exposure at an environmentally relevant concentration resulted in female-specific effects on bone as well as on plasma biomarkers of collagen synthesis and inflammation. Even a dose approximately eight times lower than the current temporary EFSA human tolerable daily intake of 4 μg/kg BW/day, appeared to induce bone stiffness reduction, bone marrow fibrosis and chronic inflammation in female rat offspring later in life.

PMID: 31326715 [PubMed - as supplied by publisher]

Differential response of lung cancer cell lines to vitamin D derivatives depending on EGFR, KRAS, p53 mutation status and VDR polymorphism.

J Steroid Biochem Mol Biol. 2019 Jul 18;:105431

Authors: Maj E, Trynda J, Maj B, Gębura K, Bogunia-Kubik K, Chodyński M, Kutner A, Wietrzyk J

Abstract
Vitamin D reveals antiproliferative activity against many types of cancer cells. Calcitriol (1,25(OH)2D3), the most active form of vitamin D3, acts mainly through the vitamin D receptor, regulating the expression of target genes. Cells with reasonable expression of VDR are considered to be sensitive to antiproliferative activity of 1,25(OH)2D3. However, a few alleles of the VDR gene are correlated with higher or lower response to 1,25(OH)2D3 treatment. The goal of our study was to establish if cells differing in EGFR, KRAS, p53 mutation status and VDR polymorphism were sensitive to antiproliferative activity of selected VDDs. In our search for the lead VDD against human lung cancer cells, we selected, for this study, low calcemic analogs of active forms of vitamin D2 and D3 that had previously shown anticancer potential. The selected cell lines revealed differential response to VDDs. The highest proliferation inhibition was observed for EGFR mutant cells while a weaker response was observed for KRAS and/or p53 mutant cells. 24,24-Dihomo-1,25(OH)2D3 (PRI-1890) showed the highest activity on the VDD-sensitive cell lines (A549, HCC827, NCI-H1299, and NCI-H1703). Therefore, PRI-1890 was selected as the lead VDD for further structure optimization. None of the VDDs used in this study showed antiproliferative activity against A-427 and Calu-3. VDR polymorphisms correlated inversely with sensitivity to the antiproliferative activity of VDDs since we observed less transcriptionally active form of VDR in HCC827 cells sensitive to VDD, while more transcriptionally active form could be observed in NCI-H358 cells that were stimulated by VDDs to proliferate. Lack of KRAS and p53 mutations in HCC827 cells may be, therefore, responsible for the higher antiproliferative activity of VDDs, while the presence of KRAS and/or p53 mutations in other cell lines might prevent antiproliferative activity even though the VDDs were transcriptionally active as assessed on the basis of increased CYP24A1 expression. VDR gene polymorphism is not directly responsible for the sensitivity of tested cells to VDDs.

PMID: 31326626 [PubMed - as supplied by publisher]

Efavirenz metabolism: Influence of polymorphic CYP2B6 variants and stereochemistry.

Drug Metab Dispos. 2019 Jul 19;:

Authors: Wang PF, Neiner A, Kharasch ED

Abstract
Efavirenz (more specifically the S-enantiomer) is a cornerstone antiretroviral therapy for treatment of HIV infection. The major primary metabolite is S-8-hydroxyefavirenz, which does not have antiretroviral activity but is neurotoxic. Cytochrome P4502B6 (CYP2B6) is the major enzyme catalyzing S-8-hydroxyefavirenz formation. CYP2B6 genetics and drug interactions are major determinants of clinical efavirenz disposition and dose adjustment. In addition, as a prototypic CYP2B6 substrate, S-efavirenz and analogs can inform on the structure, activity, catalytic mechanisms, and stereoselectivity of CYP2B6. Metabolism of R-efavirenz by CYP2B6 remains unexplored. This investigation assessed S-efavirenz metabolism by clinically relevant CYP2B6 genetic variants. This investigation also evaluated R-efavirenz hydroxylation by wild-type CYP2B6.1 and CYP2B6 variants. S-efavirenz 8-hydroxylation exhibited positive cooperativity and apparent substrate inhibition, for wild-type CYP2B6.1 and variants. Based on intrinsic clearances, relative activities for S-efavirenz 8-hydroxylation were in the order CYP2B6.4>CYP2B6.1>CYP2B6.5≈CYP2B6.17>CYP2B6.6≈CYP2B6.7≈CYP2B6.26>CYP2B6.9≈CYP2B6.19>>CYP2B6.16 and CYP2B6.18, which showed minimal activity. Rates of R-efavirenz metabolism were approximately one-tenth those of S-efavirenz, for wild-type CYP2B6.1 and variants. Based on intrinsic clearance values, there was 16-fold enantioselectivity (S>R-efavirenz) for wild type CYP2B6.1, and 6- to 21-fold differences for other CYP2B6 variants. These results show that both CYP2B6 516G>T (CYP2B6*6 and CYP2B6*9), and 983T>C (CYP2B6*16 and CYP2B6*18) polymorphisms cause canonical loss of function variants for S-efavirenz 8-hydroxylation, provide a mechanistic basis for known clinical pharmacogenetic differences in efavirenz disposition, and may predict additional clinically important variant alleles. Efavirenz is the most stereoselective CYP2B6 drug substrate yet identified and may be a useful probe for the CYP2B6 active site and catalytic mechanisms. SIGNIFICANCE STATEMENT: N/A.

PMID: 31324697 [PubMed - as supplied by publisher]

Copy number variation profiling in pharmacogenetics CYP-450 and GST genes in Colombian population.

BMC Med Genomics. 2019 Jul 19;12(1):110

Authors: Ramírez B, Niño-Orrego MJ, Cárdenas D, Ariza KE, Quintero K, Contreras Bravo NC, Tamayo-Agudelo C, González MA, Laissue P, Fonseca Mendoza DJ

Abstract
BACKGROUND: Copy Number variation (CNVs) in genes related to drug absorption, distribution, metabolism and excretion (ADME) are relevant in the interindividual variability of drug response. Studies of the CNVs in ADME genes in Latin America population are lacking. The objective of the study was to identify the genetic variability of CNVs in CYP-450 and GST genes in a subgroup of individuals of Colombian origin.
METHODS: Genomic DNA was isolated from 123 healthy individuals from a Colombian population. Multiplex Ligation-Dependent Probe Amplification (MLPA) was performed for the identification of CNVs in 40 genomic regions of 11 CYP-450 and 3 GST genes. The genetic variability, allelic and genotypic frequencies were analyzed.
RESULTS: We found that 13 out of 14 genes had CNVs: 5 (35.7%) exhibited deletions and duplications, while 8 (57.1%) presented either deletions or duplications.. 33.3% of individuals carried deletions and duplications while 49.6% had a unique type of CNV (deletion or duplication). The allelic frequencies of the CYP and GST genes were 0 to 47.6% (allele null), 0 to 17.5% (duplicated alleles) and 37 to 100% (normal alleles).
CONCLUSIONS: Our results describe, for the first time, the genomic profile of CNVs in a subgroup of Colombian population in GST and CYP-450 genes. GST genes indicated greater genetic variability than CYP-450 genes. The data obtained contributes to the knowledge of genetic profiles in Latin American subgroups. Although the clinical relevance of CNVs has not been fully established, it is a valuable source of pharmacogenetic variability data with potential involvement in the response to medications.

PMID: 31324178 [PubMed - in process]

The effect of CYP2C19 genotype-guided antiplatelet therapy on outcomes of selective percutaneous coronary intervention patients: an observational study.

Per Med. 2019 Jul 19;:

Authors: Tan K, Lian Z, Shi Y, Wang X, Yu H, Li M, Tian J, Ge Y

Abstract
Aim: To observe if personalized antiplatelet therapy according to the CYP2C19 phenotype can improve the outcomes of patients receiving selective percutaneous coronary intervention (PCI). Methods: In this observational study, 677 Chinese patients undergoing selective PCI were divided into gene group (n = 369) and conventional group (n = 308), and given antiplatelet therapy according to the CYP2C19 genotype or clinical features, respectively. Incidence of MACE (death, non-fatal myocardial infarction, and unplanned repeat revascularization) and bleeding was compared between the two groups after 18 months. Results: Diabetes, heart dysfunction and SYNTAX score (>15), but not routinely CYP2C19 genotype test-guided antiplatelet therapy, were associated with MACE. The incidence of bleeding showed no difference. Conclusion: CYP2C19 phenotype-guided antiplatelet therapy may have no influence on the outcomes of selective PCI patients. Clinical features-guided antiplatelet therapy may be reasonable.

PMID: 31322488 [PubMed - as supplied by publisher]

Identification of a key candidate gene‑phenotype network mediated by glycyrrhizic acid using pharmacogenomic analysis.

Mol Med Rep. 2019 Jul 12;:

Authors: Wang S, Li L, Shi L

Abstract
Glycyrrhizic acid (GA) is primarily used as an anti‑inflammatory agent in cases of chronic hepatitis. However, its underlying mechanisms in diverse biological processes and its reported benefits are yet to be fully elucidated. In the current study, an analytical method based on pharmacogenomics was established to mine disease‑modulatory activities mediated by GA. Five primary protein targets and 138 functional partners were identified for GA by querying open‑source databases, including Drugbank and STRING. Subsequently, GA‑associated primary and secondary protein targets were integrated into Cytoscape to construct a protein‑protein interaction network to establish connectivity. GA‑associated target genes were then clustered based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. The tumor necrosis factor axis was revealed to be a primary module regulated by GA‑associated targets. Furthermore, 12 hub genes were queried to assess their potential anti‑cancer effects using cBioPortal. The results indicated that pharmacogenomics‑based analysis improved understanding of the underlying drug‑target events of GA and provided predictive and definitive leads for future studies.

PMID: 31322195 [PubMed - as supplied by publisher]

Patient and Health Care Provider Needs and Preferences in Understanding Pharmacogenomic and Genomic Testing: A Meta-Data Analysis.

Qual Health Res. 2019 Jul 19;:1049732319858325

Authors: Veilleux S, Bouffard M, Bourque Bouliane M

Abstract
Tests that feature genomic indicators can now be used to guide the pharmacological treatment of patients. To better identify the needs and preferences of patients and health care providers in facilitating their understanding of information related to such pharmacogenomic tests (PGx), a review of literature on knowledge translation and health literacy in the context of testing was conducted. Using a grounded theory-based approach, a comparative analysis of data from 36 studies meeting the criteria for the meta-data analysis has revealed the recurrence of three principal themes: (a) knowledge and understanding of genetics and pharmacogenomics; (b) experiences with genetic, genomic, or PGx testing (decision about the test, information delivery, and understanding of test results); and (c) educational/informational resources. This synthesis sheds light on each theme from the standpoint of both patients and health care providers and suggests avenues in which to direct efforts to support the introduction of pharmacogenomic tests in current practice.

PMID: 31322055 [PubMed - as supplied by publisher]