Beneficial and Adverse Effects of cART Affect Neurocognitive Function in HIV-1 Infection: Balancing Viral Suppression against Neuronal Stress and Injury.

J Neuroimmune Pharmacol. 2019 Aug 06;:

Authors: Yuan NY, Kaul M

Abstract
HIV-associated neurocognitive disorders (HAND) persist despite the successful introduction of combination antiretroviral therapy (cART). While insufficient concentration of certain antiretrovirals (ARV) may lead to incomplete viral suppression in the brain, many ARVs are found to cause neuropsychiatric adverse effects, indicating their penetration into the central nervous system (CNS). Several lines of evidence suggest shared critical roles of oxidative and endoplasmic reticulum stress, compromised neuronal energy homeostasis, and autophagy in the promotion of neuronal dysfunction associated with both HIV-1 infection and long-term cART or ARV use. As the lifespans of HIV patients are increased, unique challenges have surfaced. Longer lives convey prolonged exposure of the CNS to viral toxins, neurotoxic ARVs, polypharmacy with prescribed or illicit drug use, and age-related diseases. All of these factors can contribute to increased risks for the development of neuropsychiatric conditions and cognitive impairment, which can significantly impact patient well-being, cART adherence, and overall health outcome. Strategies to increase the penetration of cART into the brain to lower viral toxicity may detrimentally increase ARV neurotoxicity and neuropsychiatric adverse effects. As clinicians attempt to control peripheral viremia in an aging population of HIV-infected patients, they must navigate an increasingly complex myriad of comorbidities, pharmacogenetics, drug-drug interactions, and psychiatric and cognitive dysfunction. Here we review in comparison to the neuropathological effects of HIV-1 the available information on neuropsychiatric adverse effects and neurotoxicity of clinically used ARV and cART. It appears altogether that future cART aiming at controlling HIV-1 in the CNS and preventing HAND will require an intricate balancing act of suppressing viral replication while minimizing neurotoxicity, impairment of neurocognition, and neuropsychiatric adverse effects. Graphical abstract Schematic summary of the effects exerted on the brain and neurocognitive function by HIV-1 infection, comorbidities, psychostimulatory, illicit drugs, therapeutic drugs, such as antiretrovirals, the resulting polypharmacy and aging, as well as the potential interactions of all these factors.

PMID: 31385157 [PubMed - as supplied by publisher]

HLA-DRB1*07:01 and lapatinib-induced hepatotoxicity: a systematic review and meta-analysis.

Pharmacogenomics J. 2019 Aug 06;:

Authors: Tangamornsuksan W, Kongkaew C, Scholfield CN, Subongkot S, Lohitnavy M

Abstract
Associations between HLA-DRB1*07:01 and lapatinib-induced hepatotoxicity have been reported. To consolidate the results from all available reports in scientific databases, systematic review and meta-analysis techniques were used to quantify these associations. Studies investigating associations between HLA-DRB1*07:01 and lapatinib-induced hepatotoxicity were systematically searched in PubMed, Human Genome Epidemiology Network, and the Cochrane Library. Primary outcomes were the associations between HLA-DRB1*07:01 and lapatinib-induced hepatotoxicity. Overall odds ratios (ORs) with the corresponding 95%CIs were calculated using a random-effect model to determine the associations between HLA-DRB1*07:01 and lapatinib-induced hepatotoxicity. A clear association between HLA-DRB1*07:01 and lapatinib-induced hepatotoxicity was identified in our analyses. The summary OR was 6.23 (95%CI = 4.11-9.45). Similar associations were also found in the subgroup analyses by lapatinib treatment regimens. ORs were 10.04 (95%CI = 6.15-16.39), 8.65 (95%CI = 4.52-16.58), and 3.88 (95%CI = 2.20-6.82) in the lapatinib group, lapatinib + trastuzumab group, and lapatinib + chemotherapy or lapatinib + trastuzumab + chemotherapy group, respectively. Since HLA-DRB1*07:01 is associated with lapatinib-induced hepatotoxicity, genetic screening of HLA-DRB1*07:01 in breast cancer patients prior to lapatinib therapy is warranted for patient safety. In addition, further studies should define the risk of HLA-DRB1*07:01 and lapatinib-induced hepatotoxicity in specific ethnicities.

PMID: 31383939 [PubMed - as supplied by publisher]

Effect of plasma MicroRNA on antihypertensive response to beta blockers in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) studies.

Eur J Pharm Sci. 2019 Apr 01;131:93-98

Authors: Solayman MH, Langaee TY, Gong Y, Shahin MH, Turner ST, Chapman AB, Gums JG, Boerwinkle E, Beitelshees AL, El-Hamamsy M, El-Wakeel L, Cooper-DeHoff RM, Badary OA, Johnson JA

Abstract
β-blockers show variable efficacy as antihypertensives. Herein, we evaluated plasma miRNAs as biomarkers for defining antihypertensive response to β-blockers. Expression of 22 β-blocker pharmacodynamics-related miRNAs was assessed in baseline plasma samples from 30 responders and 30 non-responders to metoprolol from the PEAR-2 study (Discovery). Logistic regression was performed to identify miRNAs significantly associated with metoprolol response. Those miRNAs were profiled in baseline plasma samples from 25 responders and 25 non-responders to atenolol from the PEAR study (validation). In discovery, miR-101, miR-27a, miR-22, miR-19a, and let-7e were significantly associated with metoprolol response (P = 0.01, 0.017, 0.025, 0.025, and 0.04, respectively). In validation, miR-19a was significantly associated with atenolol response (P = 0.038). Meta-analysis between PEAR-2 and PEAR revealed significant association between miR-19a (P = 0.004), miR-101 (P = 0.006), and let-7e (P = 0.012) and β-blocker response. Hence, miR-19a, miR-101, and let-7e, which regulate β1-adrenergic receptor and other β-blocker pharmacodynamics-related genes, may be biomarkers for antihypertensive response to β-blockers.

PMID: 30753892 [PubMed - in process]

Mitofusin 2 Is Essential for IP3-Mediated SR/Mitochondria Metabolic Feedback in Ventricular Myocytes.

Front Physiol. 2019;10:733

Authors: Seidlmayer LK, Mages C, Berbner A, Eder-Negrin P, Arias-Loza PA, Kaspar M, Song M, Dorn Ii GW, Kohlhaas M, Frantz S, Maack C, Gerull B, Dedkova EN

Abstract
Aim: Endothelin-1 (ET-1) and angiotensin II (Ang II) are multifunctional peptide hormones that regulate the function of the cardiovascular and renal systems. Both hormones increase the intracellular production of inositol-1,4,5-trisphosphate (IP3) by activating their membrane-bound receptors. We have previously demonstrated that IP3-mediated sarcoplasmic reticulum (SR) Ca2+ release results in mitochondrial Ca2+ uptake and activation of ATP production. In this study, we tested the hypothesis that intact SR/mitochondria microdomains are required for metabolic IP3-mediated SR/mitochondrial feedback in ventricular myocytes. Methods: As a model for disrupted mitochondrial/SR microdomains, cardio-specific tamoxifen-inducible mitofusin 2 (Mfn2) knock out (KO) mice were used. Mitochondrial Ca2+ uptake, membrane potential, redox state, and ATP generation were monitored in freshly isolated ventricular myocytes from Mfn2 KO mice and their control wild-type (WT) littermates. Results: Stimulation of ET-1 receptors in healthy control myocytes increases mitochondrial Ca2+ uptake, maintains mitochondrial membrane potential and redox balance leading to the enhanced ATP generation. Mitochondrial Ca2+ uptake upon ET-1 stimulation was significantly higher in interfibrillar (IFM) and perinuclear (PNM) mitochondria compared to subsarcolemmal mitochondria (SSM) in WT myocytes. Mfn2 KO completely abolished mitochondrial Ca2+ uptake in IFM and PNM mitochondria but not in SSM. However, mitochondrial Ca2+ uptake induced by beta-adrenergic receptors activation with isoproterenol (ISO) was highest in SSM, intermediate in IFM, and smallest in PNM regions. Furthermore, Mfn2 KO did not affect ISO-induced mitochondrial Ca2+ uptake in SSM and IFM mitochondria; however, enhanced mitochondrial Ca2+ uptake in PNM. In contrast to ET-1, ISO induced a decrease in ATP levels in WT myocytes. Mfn2 KO abolished ATP generation upon ET-1 stimulation but increased ATP levels upon ISO application with highest levels observed in PNM regions. Conclusion: When the physical link between SR and mitochondria by Mfn2 was disrupted, the SR/mitochondrial metabolic feedback mechanism was impaired resulting in the inability of the IP3-mediated SR Ca2+ release to induce ATP production in ventricular myocytes from Mfn2 KO mice. Furthermore, we revealed the difference in Mfn2-mediated SR-mitochondrial communication depending on mitochondrial location and type of communication (IP3R-mRyR1 vs. ryanodine receptor type 2-mitochondrial calcium uniporter).

PMID: 31379586 [PubMed]

Ferroptosis Induction in Pentylenetetrazole Kindling and Pilocarpine-Induced Epileptic Seizures in Mice.

Front Neurosci. 2019;13:721

Authors: Mao XY, Zhou HH, Jin WL

Abstract
Epilepsy is a serious neurological disorder and is characterized by recurrent and unprovoked seizures. A critical pathological factor in the seizure genesis is neuronal loss. Until now, apart from the known regulatory cell death pathways, ferroptosis is a newly discovered type of cell death with the features of iron accumulation and the excessive production of lipid reactive oxygen species (ROS). In our present work, it was illustrated that ferroptosis occurs in murine models of pentylenetetrazole (PTZ) kindling and pilocarpine (Pilo)-induced seizures. In both of these seizure models, treatment with ferroptosis inhibitor ferrostatin-1 (Fer-1) efficiently alleviates seizures. This was achieved through elevated levels of glutathione peroxidase 4 (GPX4) and glutathione (GSH) as well as inhibitions of lipid degradation products including 4-hydroxynonenal (4-HNE) and malonaldehyde (MDA), iron accumulation, and PTGS2 mRNA in the hippocampus. It was concluded that ferroptosis is involved in seizure genesis in PTZ- and Pilo-treated mice, while the suppression of ferroptosis mitigates PTZ kindling, and Pilo-induced seizures in mice.

PMID: 31379480 [PubMed]

Pharmacogenomics analysis in Chinese pediatric liver transplantation patients with renal toxicity induced by tacrolimus.

Xenobiotica. 2019 Aug 03;:1-18

Authors: Wang D, Chen X, Fu M, Xu H, Li Z

Abstract
1. Survival for pediatric liver transplantation patients is limited by nephrotoxicity of calcineurin inhibitors tacrolimus. The present study was to explore the association of genetic factors with nephrotoxicity of pediatric liver transplantation patients treated with tacrolimus. 2. Chinese pediatric liver transplantation patients under tacrolimus therapy between March 2014 and August 2018 from Children's Hospital of Fudan University were retrospectively analyzed. A total of 15 patients, including 6 patients with nephrotoxicity induced by tacrolimus and 9 patients without nephrotoxicity, were detected by pharmacogenomics (PGxOne®160). Demographic characteristics and laboratory testing were collected from medical logs. Tacrolimus blood concentrations were extracted from therapeutic drug monitoring (TDM) documents. 3. The risk of renal toxicity induced by tacrolimus in Chinese pediatric liver transplantation patients were positively associated with T allele of cytochrome P450 1A2 (CYP1A2) rs2470890 (RR =2.857, 95% confidence interval = [1.392-5.863]), A allele of dopamine D2 (DRD2) rs1076560 (RR =4.375, 95% confidence interval = [1.148-16.676]), T allele of paraoxonase-1 (PON1) rs662 (RR =2.800, 95% confidence interval= [1.184-6.622]), respectively. 4. Pharmacogenomics analysis in Chinese pediatric liver transplantation patients with renal toxicity induced by tacrolimus was firstly reported. The SNPs in 3 genes (CYP1A2, DRD2, and PON1) were associated with risk of tacrolimus-induced nephrotoxicity.

PMID: 31379240 [PubMed - as supplied by publisher]

A Pharmacogenomic Landscape in Human Liver Cancers.

Cancer Cell. 2019 Jul 16;:

Authors: Qiu Z, Li H, Zhang Z, Zhu Z, He S, Wang X, Wang P, Qin J, Zhuang L, Wang W, Xie F, Gu Y, Zou K, Li C, Li C, Wang C, Cen J, Chen X, Shu Y, Zhang Z, Sun L, Min L, Fu Y, Huang X, Lv H, Zhou H, Ji Y, Zhang Z, Meng Z, Shi X, Zhang H, Li Y, Hui L

Abstract
Liver cancers are highly heterogeneous with poor prognosis and drug response. A better understanding between genetic alterations and drug responses would facilitate precision treatment for liver cancers. To characterize the landscape of pharmacogenomic interactions in liver cancers, we developed a protocol to establish human liver cancer cell models at a success rate of around 50% and generated the Liver Cancer Model Repository (LIMORE) with 81 cell models. LIMORE represented genomic and transcriptomic heterogeneity of primary cancers. Interrogation of the pharmacogenomic landscape of LIMORE discovered unexplored gene-drug associations, including synthetic lethalities to prevalent alterations in liver cancers. Moreover, predictive biomarker candidates were suggested for the selection of sorafenib-responding patients. LIMORE provides a rich resource facilitating drug discovery in liver cancers.

PMID: 31378681 [PubMed - as supplied by publisher]

Determining Allele-Specific Protein Expression (ASPE) Using a Novel Quantitative Concatamer Based Proteomics Method.

J Proteome Res. 2018 10 05;17(10):3606-3612

Authors: Shi J, Wang X, Zhu H, Jiang H, Wang D, Nesvizhskii A, Zhu HJ

Abstract
Measuring allele-specific expression (ASE) is a powerful approach for identifying cis-regulatory genetic variants. Here, we developed a novel targeted proteomics method for the quantification of allele-specific protein expression (ASPE) based on scheduled parallel reaction monitoring (PRM) with a heavy stable isotope-labeled quantitative concatamer (QconCAT) internal protein standard. This strategy was applied to the determination of the ASPE of UGT2B15 in human livers using the common UGT2B15 nonsynonymous variant rs1902023 (i.e., Y85D) as the marker to differentiate expressions from the two alleles. The QconCAT standard contains both the wild-type tryptic peptide and the Y85D mutant peptide at a ratio of 1:1 to ensure accurate measurement of the ASPE of UGT2B15. The results from 18 UGT2B15 Y85D heterozygotes revealed that the ratios between the wild-type Y allele and the mutant D allele varied from 0.60 to 1.46, indicating the presence of cis-regulatory variants. In addition, we observed no significant correlations between the ASPE and mRNA ASE of UGT2B15, suggesting the involvement of different cis-acting variants in regulating the transcription and translation processes of the gene. This novel ASPE approach provides a powerful tool for capturing cis-genetic variants involved in post-transcription processes, an important yet understudied area of research.

PMID: 30141943 [PubMed - indexed for MEDLINE]

Genomic ancestry, CYP2D6, CYP2C9 and CYP2C19 among Latin-Americans.

Clin Pharmacol Ther. 2019 Aug 02;:

Authors: Rodrigues-Soares F, Peñas-Lledó EM, Tarazona-Santos E, Sosa-Macías M, Terán E, López-López M, Rodeiro I, Moya GE, Calzadilla LR, Ramírez-Roa R, Grazina M, Estévez-Carrizo FE, Barrantes R, LLerena A, CEIBA-Consortium of the Ibero-American Network of Pharmacogenetics and Pharmacogenomics RIBEF

Abstract
We present the distribution of CYP2D6, CYP2C9 and CYP2C19 variants and predicted phenotypes in 33 native and admixed populations from Ibero-America (n>6,000) in the context of genetic ancestry (n=3,387). Continental ancestries are the major determinants of frequencies of the increased-activity allele CYP2C19*17 and CYP2C19 gUMs (negatively associated with Native American ancestry), decreased-activity alleles CYP2D6*41 and CYP2C9*2 (positively associated with European ancestry), and decreased-activity alleles CYP2D6*17 and CYP2D6*29 (positively associated with African ancestry). For the rare alleles CYP2C9*2 and CYPC19*17, European admixture accounts for their presence in Native American populations, but rare alleles CYP2D6*5 (null-activity), CYP2D6-multiplication alleles (increased activity) and CYP2C9*3 (decreased-activity) were present in the pre-Columbian Americas. The study of a broad spectrum of Native American populations from different ethno-linguistic groups shows how autochthonous diversity shaped the distribution of pharmaco-alleles and give insights on the prevalence of clinically relevant phenotypes associated with drugs such as paroxetine, tamoxifen, warfarin and clopidogrel. This article is protected by copyright. All rights reserved.

PMID: 31376146 [PubMed - as supplied by publisher]

Sleep Pharmacogenetics: The Promise of Precision Medicine.

Sleep Med Clin. 2019 Sep;14(3):317-331

Authors: Krystal AD, Prather AA

Abstract
Pharmacogenetics is the branch of personalized medicine concerned with the variability in drug response occurring because of heredity. Advances in genetics research, and decreasing costs of gene sequencing, are promoting tremendous growth in pharmacogenetics in all areas of medicine, including sleep medicine. This article reviews the body of research indicating that there are genetic variations that affect the therapeutic actions and adverse effects of agents used for the treatment of sleep disorders to show the potential of pharmacogenetics to improve the clinical practice of sleep medicine.

PMID: 31375201 [PubMed - in process]

Propolis Reduces the Expression of Autophagy-Related Proteins in Chondrocytes under Interleukin-1β Stimulus.

Int J Mol Sci. 2019 Aug 01;20(15):

Authors: Arias C, Saavedra N, Saavedra K, Alvear M, Cuevas A, Stuchi Maria-Engler S, Abdalla DSP, Salazar LA

Abstract
BACKGROUND: Osteoarthritis (OA) is a progressive and multifactorial disease that is associated with aging. A number of changes occur in aged cartilage, such as increased oxidative stress, decreased markers of healthy cartilage, and alterations in the autophagy pathway. Propolis extracts contain a mixture of polyphenols and it has been proved that they have high antioxidant capacity and could regulate the autophagic pathway. Our objective was to evaluate the effect of ethanolic extract of propolis (EEP) on chondrocytes that were stimulated with IL-1β.
METHODS: Rabbit chondrocytes were isolated and stimulated with IL-1β and treated with EEP. We evaluated cell viability, nitric oxide production, healthy cartilage, and OA markers, and the expression of three proteins associated with the autophagy pathway LC3, ATG5, and AKT1.
RESULTS: The EEP treatment reduces the expression of LC3, ATG5, and AKT1, reduces the production of nitric oxide, increases the expression of healthy markers, and reduces OA markers.
CONCLUSIONS: These results suggest that treatment with EEP in chondrocytes that were stimulated with IL-1β has beneficial effects, such as a decrease in the expression of proteins associated with autophagy, MMP13, and production of nitric oxide, and also increased collagen II.

PMID: 31374866 [PubMed - in process]

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pharmacogenomics

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20 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

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PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

HNF1A mutation in a Thai patient with maturity-onset diabetes of the young: A case report.

World J Diabetes. 2019 Jul 15;10(7):414-420

Authors: Plengvidhya N, Tangjittipokin W, Teerawattanapong N, Narkdontri T, Yenchitsomanus PT

Abstract
BACKGROUND: Maturity-onset diabetes of the young (MODY) is the most common form of monogenic diabetes. The disease is transmitted in autosomal dominant mode and diabetes is usually diagnosed before age 25 year. MODY 3 is caused by mutation of hepatocyte nuclear factor (HNF) 1A genes and is the most common MODY subtype. Diagnosis of MODY 3 is crucial since glycemic control can be accomplished by very low dose of sulfonylurea. In this report we described a Thai MODY 3 patient who had excellence plasma glucose control by treating with glicazide 20 mg per day and insulin therapy can be discontinued.
CASE SUMMARY: A 31-year-old woman was diagnosed diabetes mellitus at 14 years old. The disease was transmitted from her grandmother and mother compatible with autosomal dominant inheritance. Sanger sequencing of proband's DNA identified mutation of HNF1A at codon 203 which changed amino acid from arginine to cysteine (R203C). This mutation was carried only by family members who have diabetes. The patient has been treated effectively with a combination of oral hypoglycemic agents and must include a very low dose of glicazide (20 mg/d). Insulin therapy was successfully discontinued.
CONCLUSION: We demonstrated a first case of pharmacogenetics in Thai MODY 3 patient. Our findings underscore the essential role of molecular genetics in diagnosis and guidance of appropriate treatment of diabetes mellitus in particular patient.

PMID: 31363388 [PubMed]

Quality Control Measures and Validation in Gene Association Studies: Lessons for Acute Illness.

Shock. 2019 Jul 30;:

Authors: Cohen M, Lamparello AJ, Schimunek L, El-Dehaibi F, Namas RA, Xu Y, Kaynar AM, Billiar TR, Vodovotz Y

Abstract
Acute illness is a complex constellation of responses involving dysregulated inflammatory and immune responses, which are ultimately associated with multiple organ dysfunction. Gene association studies have associated single-nucleotide polymorphisms (SNPs) with clinical and pharmacological outcomes in a variety of disease states, including acute illness. With approximately 4-5 million SNPs in the human genome and recent studies suggesting that a large portion of SNP studies are not reproducible, we suggest that the ultimate clinical utility of SNPs in acute illness depends on validation and quality control measures. To investigate this issue, in December 2018 and January 2019 we searched the literature for peer-reviewed studies reporting data on associations between SNPs and clinical outcomes and between SNPs and pharmaceuticals (i.e. pharmacogenomics) published between January 2011 to February 2019. We review key methodologies and results from a variety of clinical and pharmacological gene association studies, including trauma and sepsis studies, as illustrative examples on current SNP association studies. In this review article, we have found three key points which strengthen the potential accuracy of SNP association studies in acute illness and other diseases: 1) providing evidence of following a protocol quality control method such as the one in Nature Protocols (22) or the OncoArray QC Guidelines (21); 2) enrolling enough patients to have large cohort groups; and 3) validating the SNPs using an independent technique such as a second study using the same SNPs with new patient cohorts. Our survey suggests the need to standardize validation methods and SNP quality control measures in medicine in general, and specifically in the context of complex disease states such as acute illness.

PMID: 31365490 [PubMed - as supplied by publisher]

Determination of Perampanel in Dried Plasma Spots: Applicability to Therapeutic Drug Monitoring.

Ther Drug Monit. 2019 Jul 29;:

Authors: Franco V, Baruffi K, Francesca Crema RM, Fattore C, Romigi A, Valentina G, Tartara E, Maurizio E, D'Avolio A, Perucca E

Abstract
BACKGROUND: Although therapeutic drug monitoring of antiepileptic drugs (AEDs) is typically based on analysis of plasma samples, alternative matrices such as dried plasma spots (DPSs) may offer specific advantages. The aims of this work were to: i) develop and validate a bioanalytical method for the quantitative determination of the second-generation AED perampanel in DPSs; ii) assess short- and long-term stability of perampanel in DPSs; and iii) test the clinical applicability of the developed method.
METHODS: Two hundred microliters of plasma were dispensed on a glass paper filter and dried. Glass paper filter discs were then inserted into clean tubes. After addition of the internal standard (i.e., promethazine), the analytes were extracted with 5 mL methanol, dried at room temperature (23±2°C), and reconstituted. Separation and quantification were achieved on two serial reverse-phase monolithic columns connected to a UV detector (λ=320 nm).
RESULTS: Calibration curves were linear in the validated concentration range (25-1000 ng/mL). Intra-day and inter-day accuracy were in the range of 99.2-111.4%, whereas intra-day and inter-day precision (CV) ranged from 3.4 to 8.6%. The lowest limit of quantitation was 25 ng/mL. The stability of the analyte in DPSs was assessed and confirmed under different storage conditions. Perampanel concentrations estimated in DPS samples from patients receiving therapeutic doses were equivalent to those measured in plasma samples.
CONCLUSIONS: This simple method enables the quantitation of perampanel in DPSs with adequate accuracy, precision, specificity, and sensitivity. The short- and long-term stability of perampanel in DPSs is highly beneficial for sample shipment or storage at ambient temperature. Moreover, DPSs decreases the costs associated with storage and transportation compared with conventional wet samples.

PMID: 31365481 [PubMed - as supplied by publisher]

Drug-induced interstitial lung disease: role of pharmacogenetics in predicting cytotoxic mechanisms and risks of side effects.

Curr Opin Pulm Med. 2019 Sep;25(5):468-477

Authors: Jessurun NT, Drent M, van Puijenbroek EP, Bekers O, Wijnen PA, Bast A

Abstract
PURPOSE OF REVIEW: The diagnosis of drug-induced interstitial lung disease (DI-ILD) is challenging and mainly made by exclusion of other possible causes. Toxicity can occur as a cause of drug(s) or drug-drug interactions. In this review, we summarize the possible role of pharmacogenetics of metabolizing enzymes in DI-ILD.
RECENT FINDINGS: Knowledge of the genetic predispositions of enzymes involved in drug metabolization and their relation with proposed cytotoxic mechanisms of DI-ILD, in particular direct cell toxicity and free oxygen radical production is increasing. The cytochrome P450 enzyme family and other enzymes play an important role in the metabolism of all sorts of ingested, injected, or inhaled xenobiotic substances. The liver is the major site for metabolism. Metabolic cytotoxic mechanisms have however also been detected in lung tissue. Polymorphisms in genes coding for enzymes that influence metabolic activity may lead to localized (toxic) reactions and tissue damage. This knowledge may be helpful in preventing the risk of DI-ILD.
SUMMARY: Drug toxicity can be the consequence of absence or very poor enzyme activity, especially if no other metabolic route is available. In the case of reduced enzyme activity, it is recommended to reduce the dose or to prescribe an alternative drug, which is metabolized by a different, unaffected enzyme system to prevent toxic side effects. However, enhanced enzyme activity may lead to excessive formation of toxic and sometimes reactive metabolites. Therefore, knowing a patient's drug-metabolizing profile before drug prescription is a promising way to prevent or explain DI-ILD.

PMID: 31365381 [PubMed - in process]

Long-term Exposure of 4-hydroxyestradiol Induces the Cancer Cell Characteristics via Upregulating CYP1B1 in MCF-10A Cells.

Toxicol Mech Methods. 2019 Jul 31;:1-18

Authors: Lanxiang W, Bin W, Ge X, Yutang H, Chunjie W, Honghao Z

Abstract
Life-long estrogen exposure is one of the major risk factors in the development and progression of breast cancer. However, little is known about the molecular mechanisms, by which chronic exposure to estrogen contributes to breast carcinogenesis. The aim of the present study was to investigate the effects of long-term exposure with 4-hydroxyestradiol (4-OHE2) on acquired cancer characteristics of human mammary epithelial MCF-10A cells. The possible regulators were further studied in chronic 4-OHE2-treated MCF-10A cells.We observed that MCF-10A cells long-term exposed to 4-OHE2 acquire the characteristics of cancer cells, such as enhanced cell growth, EMT properties, and increased migration and invasiveness. Moreover, the expression of CYP1B1 was significantly elevated in long-term 4-OHE2-treated MCF-10A cells. Block of CYP1B1 significantly reduced the cancer cell characteristics in long-term 4-OHE2-treated MCF-10A cells. Our results indicated that 4-OHE2 mediated enhanced cancer cell characteristics in mammary epithelial cells are an important key event for breast carcinogenesis process. CYP1B1 partially contributes to the 4-OHE2 induced cancer cell characteristics in MCF-10A cells. Targeting CYP1B1 might offer a new strategy for the treatment of estrogen-induced breast cancer.

PMID: 31364906 [PubMed - as supplied by publisher]

HSPB1 rs2070804 polymorphism is associated with the depth of primary tumor.

J Cell Biochem. 2019 Jul 30;:

Authors: Hung CS, Huang CY, Hsu YW, Makondi PT, Chang WC, Chang YJ, Wang JY, Wei PL

Abstract
BACKGROUND: Colorectal cancer (CRC) is the third most common cancer in the world. Genome-wide association studies are a powerful method to analyze the status of single-nucleotide polymorphisms (SNPs) in specific genes. Heat shock proteins (HSPs) were found to be involved in the cancer progression and chemoresistance. However, there is still no further study about polymorphisms of HSP beta-1 (HSPB1) in colorectal cancer. We proposed the SNP of HSPB1 may be correlated with the progression and metastasis in colon cancer.
METHODS: We recruited 379 colorectal cancer patients and categorized as four stages following the UICC TNM system. Then, we selected tagging SNPs of HSPB1 by 10% minimum allelic frequency in Han Chinese population from the HapMap database and analyze with the Chi-square test.
RESULTS: We demonstrated the association of HSPB1 genetic polymorphisms rs2070804 with tumor depth with colorectal cancer. But, there is a lack of association between HSPB1 genetic polymorphisms and colorectal cancer invasion, recurrence or metastasis.
CONCLUSIONS: The polymorphisms of HSPB1 seemed to change the tumor behavior of colorectal cancer. HSPB1 rs2070804 polymorphism is associated with the depth of the primary tumor. But, there is no further correlation with other to the clinical parameters such as cancer invasiveness, local recurrence, or distant metastasis.

PMID: 31364192 [PubMed - as supplied by publisher]

Acylpeptide hydrolase (APEH) sequence variants with potential impact on the metabolism of the antiepileptic drug valproic acid.

Metab Brain Dis. 2019 Jul 30;:

Authors: Tsortouktzidis D, Grundke K, Till C, Korwitz-Reichelt A, Sass JO

Abstract
Acylpeptide hydrolase (APEH) is a serine protease involved in the recycling of amino acids from acylated peptides. Beyond that, APEH participates in the metabolism of the antiepileptic drug valproic acid (2-propylpentanoic acid; VPA) by catalyzing the hydrolysis of the VPA metabolite valproylglucuronide (VPA-G) to its aglycon. It has been shown that the inhibition of APEH by carbapenem antibiotics decreases therapeutic VPA levels by enhancing the urinary elimination of VPA in form of VPA-G. As various sequence variants of the APEH gene (which encodes the APEH protein) are listed in databases, but have not been functionally characterized yet, we assume, that some APEH sequence variants may have pharmacogenetic relevance due to their impaired cleavage of VPA-G. APEH sequence variants predicted to affect enzyme activity were selected from databases, and overexpressed in HEK293 cells (stable transfection), a cell line derived from human embryonic kidney cells. APEH activity in cell homogenates was determined spectrophotometrically by monitoring the hydrolysis of the synthetic substrate N-acetyl-L-alanine-nitroanilide. APEH enzyme activity and protein expression of the sequence variants were compared with those of APEH with the reference sequence. Three out of five tested missense sequence variants resulted in a considerable decrease of enzyme activity assessed with the standard substrate N-acetyl-L-alanine-nitroanilide, suggesting an effect on pharmacokinetics of VPA. Our work underlines the need to consider the APEH genotype in investigations of altered VPA metabolism.

PMID: 31363986 [PubMed - as supplied by publisher]