Pharmacotherapy of Autism Spectrum Disorder: Results from the Randomized BAART Clinical Trial.

Pharmacotherapy. 2019 May 07;:

Authors: De Vane CL, Charles JM, Abramson RK, Williams JE, Carpenter LA, Raven S, Gwynette F, Stuck CA, Geesey ME, Bradley C, Donovan JL, Hall AG, Sherk ST, Powers NR, Spratt E, Kinsman A, Kruesi MJ, Bragg JE

Abstract
STUDY OBJECTIVE: The objective of this trial-Biomarkers in Autism of Aripiprazole and Risperidone Treatment (BAART)-was to provide support and guidance for an evidence-based approach for the selection and monitoring of initial pharmacotherapy in patients with autism by assessing predictors of efficacy, tolerability, and safety.
DESIGN: Randomized, double-blind, parallel-group study.
SETTING: Three academic medical centers and a single private pediatric practice.
PATIENTS: Eighty children or adolescents (aged 6-17 years) with autistic disorder were enrolled, and 61 patients were randomized to study drug. Of those patients, 51 completed the 10-week trial, and 31 completed an optional 12-week blinded extension phase.
INTERVENTION: All patients were treated with 2 weeks of placebo before random assignment to receive aripiprazole (31 patients) or risperidone (30 patients) for 10 weeks. Sixteen placebo responders (20%) were excluded from further analysis. Drug dosing followed United States Food and Drug Administration (FDA) labeling, and weekly dosage adjustments were allowed until week 4; patients were then maintained on a fixed dose for 6 additional weeks.
MEASUREMENTS AND MAIN RESULTS: Safety, physical, and psychological assessments were recorded weekly or every two weeks. No significant differences in severity of illness between the aripiprazole and risperidone groups were noted at baseline. All patients significantly improved on the Aberrant Behavior Checklist irritability subscale after one week and continued for the remaining 9 weeks and the extension phase. Improvement was greatest in the risperidone group at every assessment period and was statistically significantly better than that in the aripiprazole group at weeks 3 and 6 (p<0.05). No dose-limiting adverse events occurred during the dose-titration period. Mean weight gain in the aripiprazole group was significantly less than that in the risperidone group at week 4 (0.62 vs 1.38 kg, p=0.033) and week 10 (1.61 vs 3.31 kg, p<0.001), but the difference became nonsignificant for the 31 patients completing the 3-month extension phase (4.36 vs 5.55 kg, p=0.26).
CONCLUSION: Pharmacotherapy of patients with autism spectrum disorder resulted in behavioral improvement within one week and lasted at least 22 weeks. Weight gain occurred to a greater degree with risperidone than aripiprazole initially, but the differences became nonsignificant by the end of the trial. Our trial supports previous results of drug efficacy and safety in patients with autism spectrum disorder from other trials and extends the evidence-based support for choosing an FDA-approved drug for initial pharmacotherapy for autism spectrum disorder. This article is protected by copyright. All rights reserved.

PMID: 31063671 [PubMed - as supplied by publisher]

Pharmacogenetics in personalised drug therapy.

Tidsskr Nor Laegeforen. 2019 May 06;:

Authors: Tuv SS, Nordal K, Vethe NT, Bergan S

PMID: 31062549 [PubMed - as supplied by publisher]

[Fission Yeast as a Model System for Studying Cancer Signaling and Drug Discovery: Discovery of ACA-28 as a Novel Inducer of ERK-dependent Apoptosis Reveals a New Cancer Therapy].

Yakugaku Zasshi. 2019;139(5):753-758

Authors: Sugiura R

Abstract
Mitogen-activated protein kinase (MAPK) pathways are evolutionarily conserved kinase modules that link extracellular signals to the machinery that controls fundamental cellular processes such as growth, proliferation, differentiation, and apoptosis. The Ras/Raf/MEK/ERK MAPK pathway is one of the most studied of the mammalian MAPK pathways and has attracted intense research interest because of its critical involvement in the regulation of cell proliferation. The mutational activation of upstream signaling components that constitutively activate ERK MAPKs as seen in various primary tumor samples has validated this pathway for drug discovery. The fission yeast Schizosaccharomyces pombe is an important tool for cancer research. This well-studied model organism has enabled groundbreaking, Nobel Prize-winning discoveries and has provided insights into how both normal and cancerous cells grow and divide. We performed chemical genetic screening using a fission yeast phenotypic assay and demonstrated that ACA-28, a synthetic derivative of 1'-acetoxychavicol acetate (ACA), effectively inhibited the growth of melanoma cancer cells wherein ERK MAPK signaling is hyperactivated due to mutations in the upstream activating regulators. Importantly, the growth of normal human epidermal melanocytes was less affected by ACA-28. In addition, ACA-28 specifically induced apoptosis in NIH/3T3 cells oncogenically transformed with HER2/ErbB2 but not in the parental cells. Notably, the ACA-28-induced apoptosis was abrogated when ERK activation was blocked with the specific MEK inhibitor U0126. Consistently, ACA-28 more strongly stimulated ERK phosphorylation in melanoma cells as compared with normal human epidermal melanocytes. ACA-28 might serve as a promising seed compound to combat ERK-dependent cancers by stimulating oncogenic signaling.

PMID: 31061345 [PubMed - in process]

[Innovative Cancer Therapeutics Propelled by Model Organisms: Paradigm Shift in Drug Discovery and Diagnosis for Cancer].

Yakugaku Zasshi. 2019;139(5):731-732

Authors: Sugiura R

PMID: 31061342 [PubMed - in process]

Medial Prefrontal Cortex-Pontine Nuclei Projections Modulate Suboptimal Cue-Induced Associative Motor Learning.

Cereb Cortex. 2018 03 01;28(3):880-893

Authors: Wu GY, Liu SL, Yao J, Sun L, Wu B, Yang Y, Li X, Sun QQ, Feng H, Sui JF

Abstract
Diverse and powerful mechanisms have evolved to enable organisms to modulate learning and memory under a variety of survival conditions. Cumulative evidence has shown that the prefrontal cortex (PFC) is closely involved in many higher-order cognitive functions. However, when and how the medial PFC (mPFC) modulates associative motor learning remains largely unknown. Here, we show that delay eyeblink conditioning (DEC) with the weak conditioned stimulus (wCS) but not the strong CS (sCS) elicited a significant increase in the levels of c-Fos expression in caudal mPFC. Both optogenetic inhibition and activation of the bilateral caudal mPFC, or its axon terminals at the pontine nucleus (PN) contralateral to the training eye, significantly impaired the acquisition, recent and remote retrieval of DEC with the wCS but not the sCS. However, direct optogenetic activation of the contralateral PN had no significant effect on the acquisition, recent and remote retrieval of DEC. These results are of great importance in understanding the elusive role of the mPFC and its projection to PN in subserving the associative motor learning under suboptimal learning cue.

PMID: 28077515 [PubMed - indexed for MEDLINE]

Polymorphisms in Dopaminergic Genes in Schizophrenia and Their Implications in Motor Deficits and Antipsychotic Treatment.

Front Neurosci. 2019;13:355

Authors: Ye J, Ji F, Jiang D, Lin X, Chen G, Zhang W, Shan P, Zhang L, Zhuo C

Abstract
Dopaminergic system dysfunction is involved in schizophrenia (SCZ) pathogenesis and can mediate SCZ-related motor disorders. Recent studies have gradually revealed that SCZ susceptibility and the associated motor symptoms can be mediated by genetic factors, including dopaminergic genes. More importantly, polymorphisms in these genes are associated with both antipsychotic drug sensitivity and adverse effects. The study of genetic polymorphisms in the dopaminergic system may help to optimize individualized drug strategies for SCZ patients. This review summarizes the current progress about the involvement of the dopamine system in SCZ-associated motor disorders and the motor-related adverse effects after antipsychotic treatment, with a special focus on polymorphisms in dopaminergic genes. We hypothesize that the genetic profile of the dopaminergic system mediates both SCZ-associated motor deficits associated and antipsychotic drug-related adverse effects. The study of dopaminergic gene polymorphisms may help to predict drug efficacy and decrease adverse effects, thereby optimizing treatment strategies.

PMID: 31057354 [PubMed]

Pharmacogenetic Testing: Why Is It So Disappointing?

J Psychosoc Nurs Ment Health Serv. 2019 Apr 01;57(4):9-12

Authors: Limandri BJ

Abstract
Pharmacogenetic testing to aid in making decisions about prescribing medications was approved by the U.S. Food and Drug Administration in 2005 and gradually became a common practice. However, an innovation that was thought to help individualize prescribing psychotropic medications with fewer trials and errors soon became a disappointment to clinicians. Current pharmacogenetic testing assesses how the liver metabolizes drugs through the cytochrome p 450 system; however, much of the variability in how a drug affects an individual also relies on the pharmacodynamics of the drug (i.e., the specific ways the drug changes the body). The current article discusses the advantages and disadvantages of pharmacogenetic testing to aid in prescribing psychotropic medications. [Journal of Psychosocial Nursing and Mental Health Services, 57(4), 9-12.].

PMID: 30933297 [PubMed - indexed for MEDLINE]

Drug-Drug Interactions With Oral Antineoplastic Agents.

JAMA Oncol. 2017 06 01;3(6):736-738

Authors: Parsad S, Ratain MJ

PMID: 27737450 [PubMed - indexed for MEDLINE]

AR-V7 and AR-FL expression is associated with clinical outcome: a translational study in patients with castrate resistant prostate cancer.

BJU Int. 2019 May 04;:

Authors: Del Re M, Crucitta S, Sbrana A, Rofi E, Paolieri F, Gianfilippo G, Galli L, Falcone A, Morganti R, Porta C, Efstathiou E, van Schaik R, Jenster G, Danesi R

Abstract
OBJECTIVES: To investigate if full-length androgen receptor (AR-FL) is associated with resistance to AR-directed therapy independently and/or combined with AR splice variant 7 (AR-V7).
PATIENTS AND METHODS: Plasma samples were prospectively collected from 73 patients with CRPC before first or second-line AR-directed therapy. mRNA was isolated from exosomes and AR-FL and AR-V7 were analyzed by ddPCR.
RESULTS: AR-FL was detected in all patients while 22% were AR-V7+ at baseline. AR-FL expression was significantly higher in AR-V7+ vs AR-V7- patients (p<0.0001). Stratifying patients by tertiles for AR-FL expression, PFS was 22 vs 18 vs 4 months for lower vs intermediate vs higher tertile, respectively (p=0.0003). Median PFS and OS were significantly longer in AR-V7- vs AR-V7+ patients (20 vs 4 months, p<0.0001; not reached vs 9 months, p<0.0001, respectively).
CONCLUSIONS: Resistance to AR-directed therapy is associated with the presence of AR-V7; however, AR-FL expression may help better refine response and survival of patients to AR-directed therapy. Both biomarkers, if validated in prospective trials, may be used to select the best treatment strategy. This article is protected by copyright. All rights reserved.

PMID: 31055861 [PubMed - as supplied by publisher]

Creatine based polymer for codelivery of bioengineered MicroRNA and chemodrugs against breast cancer lung metastasis.

Biomaterials. 2019 Apr 26;210:25-40

Authors: Xu J, Sun J, Ho PY, Luo Z, Ma W, Zhao W, Rathod SB, Fernandez CA, Venkataramanan R, Xie W, Yu AM, Li S

Abstract
Metastasis is the major cause for breast cancer related mortality. The combination of miRNA-based therapy and chemotherapy represents a promising approach against breast cancer lung metastasis. The goal of this study is to develop an improved therapy that co-delivers a novel bioengineered miRNA prodrug (tRNA-mir-34a) and doxorubicin (DOX) via a multifunctional nanomicellar carrier that is based on a conjugate of amphiphilic copolymer POEG-VBC backbone with creatine, a naturally occurring cationic molecule. Co-delivery of DOX leads to more effective processing of tRNA-mir-34a into mature miR-34a and down-regulation of target genes. DOX + tRNA-mir-34a/POEG-PCre exhibits potent synergistic anti-tumor and anti-metastasis activity in vitro and in vivo. Interestingly, the enhanced immune response contributes to the overall antitumor efficacy. POEG-PCre may represent a safe and effective delivery system for an optimal chemo-gene combination therapy.

PMID: 31054369 [PubMed - as supplied by publisher]

DPYD and Fluorouracil-Based Chemotherapy: Mini Review and Case Report.

Pharmaceutics. 2019 May 01;11(5):

Authors: Wigle TJ, Tsvetkova EV, Welch SA, Kim RB

Abstract
5-Fluorouracil remains a foundational component of chemotherapy for solid tumour malignancies. While considered a generally safe and effective chemotherapeutic, 5-fluorouracil has demonstrated severe adverse event rates of up to 30%. Understanding the pharmacokinetics of 5-fluorouracil can improve the precision medicine approaches to this therapy. A single enzyme, dihydropyrimidine dehydrogenase (DPD), mediates 80% of 5-fluorouracil elimination, through hepatic metabolism. Importantly, it has been known for over 30-years that adverse events during 5-fluorouracil therapy are linked to high systemic exposure, and to those patients who exhibit DPD deficiency. To date, pre-treatment screening for DPD deficiency in patients with planned 5-fluorouracil-based therapy is not a standard of care. Here we provide a focused review of 5-fluorouracil metabolism, and the efforts to improve predictive dosing through screening for DPD deficiency. We also outline the history of key discoveries relating to DPD deficiency and include relevant information on the potential benefit of therapeutic drug monitoring of 5-fluorouracil. Finally, we present a brief case report that highlights a limitation of pharmacogenetics, where we carried out therapeutic drug monitoring of 5-fluorouracil in an orthotopic liver transplant recipient. This case supports the development of robust multimodality precision medicine services, capable of accommodating complex clinical dilemmas.

PMID: 31052357 [PubMed]

Pharmacogenetic Tests in Reducing Accesses to Emergency Services and Days of Hospitalization in Bipolar Disorder: A 2-Year Mirror Analysis.

J Pers Med. 2019 Apr 30;9(2):

Authors: Callegari C, Isella C, Caselli I, Poloni N, Ielmini M

Abstract
Despite the enormous costs associated to mood disorders', few studies evaluate potential cost saving from the use of pharmacogenetic tests (PGT). This study compares 12 months before the execution of the PGT versus 12 months after, in terms of number and days of hospitalization and accesses to emergency services, in a sample of 30 patients affected by bipolar disorder. Secondarily, the study gives an economic value to the data based on the diagnosis-related group (DRG). Patients included in the study were required to be aged ≥18 years, sign an informed consent, have a score of Clinical Global Impression item Severity (CGIs) ≥3, and have a discordant therapy compared to the PGT in the 12 months preceding it and a therapy consistent with it for the following 12 months. Cost saving has been evaluated by paired t-tests in a mirror analysis. Statistically significant differences in all the comparisons (p < 0.0001) emerged. Important cost saving emerged after the use of PGT (€148,920 the first year versus €39,048 the following year). Despite the small sample size and lack of a control group in this study, the potential role of PGT in cost saving for the treatment of bipolar disorder treatment emerged. To confirm this result, larger and clinical trials are needed.

PMID: 31052247 [PubMed]

Pharmacogenomics in dermatology: tools for understanding gene-drug associations.

Semin Cutan Med Surg. 2019 Mar 01;38(1):E19-E24

Authors: Daneshjou R, Huddart R, Klein TE, Altman RB

Abstract
Pharmacogenomics aims to associate human genetic variability with differences in drug phenotypes in order to tailor drug treatment to individual patients. The massive amount of genetic data generated from large cohorts of patients with variable drug phenotypes have led to advances in this field. Understanding the application of pharmacogenomics in dermatology could inform clinical practice and provide insight for future research. The Pharmacogenomics Knowledge Base and the Clinical Pharmacogenetics Implementation Consortium are among the resources to help clinicians and researchers navigate the many gene-drug associations that have already been discovered. The implementation of clinical pharmacogenomics within health care systems remains an area of ongoing development. This review provides an introduction to the field of pharmacogenomics and to current pharmacogenomics resources using examples of gene-drug associations relevant to the field of dermatology.

PMID: 31051019 [PubMed - in process]

Developing Pharmacogenomic Reports: Insights from Patients and Clinicians.

Clin Transl Sci. 2018 05;11(3):289-295

Authors: Jones LK, Kulchak Rahm A, Gionfriddo MR, Williams JL, Fan AL, Pulk RA, Wright EA, Williams MS

Abstract
Increasingly, for a variety of indications, patients have their genomes sequenced and actionable results returned. A subset of returned results is pharmacogenomic (PGx) variants involved in the metabolism or action of medications. Although the impact of these variants on health is well-documented, little research exists on how to communicate these findings to patients and clinicians. We conducted semistructured interviews with end users to understand how best to communicate PGx results. Overall, patients and clinicians had similar opinions regarding report content, delivery, and application. Unique concerns specific to each stakeholder group were also expressed. Patients wanted an easy-to-understand individualized report that clinicians utilized to guide their care. Clinicians wanted reports that were easy-to-use, actionable, and integrated into their workflow. Implementation of these reports in a clinical setting will allow for broader user feedback and iterative improvement.

PMID: 29316365 [PubMed - indexed for MEDLINE]

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The increase in activating EGFR mutation in plasma is an early biomarker to monitor response to osimertinib: a case report.

BMC Cancer. 2019 Apr 30;19(1):410

Authors: Del Re M, Rofi E, Cappelli C, Puppo G, Crucitta S, Valeggi S, Chella A, Danesi R, Petrini I

Abstract
BACKGROUND: Systemic treatment of advanced non-small cell lung cancer (NSCLC) has changed dramatically since the introduction of targeted therapies. The analysis of circulating tumor DNA (ctDNA) is a valuable approach to monitor the clonal evolution of tumors during treatment with EGFR-tyrosine kinase inhibitors (TKIs) and to detect resistance mutations.
CASE PRESENTATION: A NSCLC patient with exon 19 deletion (ex19del) of EGFR was treated with osimertinib after multiple lines of treatment and obtained a partial response that lasted over 26 months. Blood was collected at each visit and ctDNA was extracted to monitor ex19del by digital droplet PCR. Within a few weeks from the beginning of osimertinib, ex19del disappeared from plasma but appeared again and steadily increased a few months later anticipating tumor progression. Interestingly, the change in ex19del was much more pronounced than other mutations, since T790M appeared 3 months after the increase of ex19del, and C797S was detectable a few weeks before clinical disease progression. Then the patient received cytotoxic chemotherapy, which was associated with a decrease in ex19del and disappearance of T790M and C797S; however, at disease progression, all EGFR mutations increased again in plasma together with MET amplification which was detected by NGS.
CONCLUSIONS: The measurement of ex19del changes in ctDNA is a simple and sensitive approach to monitor clinical outcome to osimertinib and, potentially, to other therapeutic interventions.

PMID: 31039766 [PubMed - in process]

Role of Genomic Biomarkers in Increasing Fetal Hemoglobin Levels Upon Hydroxyurea Therapy and in β-Thalassemia Intermedia: A Validation Cohort Study.

Hemoglobin. 2019 Apr 30;:1-7

Authors: Kolliopoulou A, Siamoglou S, John A, Sgourou A, Kourakli A, Symeonidis A, Vlachaki E, Chalkia P, Theodoridou S, Ali BR, Katsila T, Patrinos GP, Papachatzopoulou A

Abstract
Hemoglobinopathies exhibit a remarkable phenotypic diversity in terms of disease severity, while individual genetic background plays a key role in differential response to drug treatment. In the last decade, genomic variants in genes located within, as well as outside the human β-globin cluster have been shown to be significantly associated with Hb F increase, in relation to hydroxyurea (HU) therapy in patients with these diseases. Here, we aim to determine the effect of genomic variants located in genes, such as MAP3K5, ASS1, NOS2A, TOX, PDE7B, NOS1, FLT1 and ARG2, previously shown to modulate fetal hemoglobin (Hb F) levels in patients with β type hemoglobinopathies and reflecting disease severity and response to HU therapy in an independent cohort of Greek patients with these diseases. We recruited and genotyped 45 β-thalassemia patients (β-thal), either transfusion-dependent (TDT) or non transfusion-dependent (NTDT), 42 Hb S (HBB: c.20A>T)-β-thal compound heterozygotes, who were treated with HU, as well as 53 healthy individuals, all of Hellenic origin. Our study showed that genomic variants of the MAP3K5, NOS2A and ARG2 gene are associated with HU therapy efficacy in Hb S-β-thal compound heterozygotes. We have also shown that FLT1 and ARG2 genomic variants are associated with the mild phenotype of NTDT patients. Our findings provide evidence that MAP3K5, NOS2A, ARG2 and FLT1 genomic variants could be considered as genomic biomarkers to predict HU therapy efficacy in Hb S-β-thal compound heterozygotes and also to describe disease severity in patients with β type hemoglobinopathies.

PMID: 31039620 [PubMed - as supplied by publisher]

Estradiol metabolites as biomarkers of endometrial cancer prognosis after surgery.

J Steroid Biochem Mol Biol. 2018 04;178:45-54

Authors: Audet-Delage Y, Grégoire J, Caron P, Turcotte V, Plante M, Ayotte P, Simonyan D, Villeneuve L, Guillemette C

Abstract
Endometrial cancer (EC) is the most common gynecologic malignancy prevailing after menopause. Defining steroid profiles may help predict the risk of recurrence after hysterectomy, which remains limited due to the lack of reliable markers. Adrenal precursors, androgens, parent estrogens and catechol estrogen metabolites were measured by mass spectrometry (MS) in preoperative serums and those collected one month after hysterectomy from 246 newly diagnosed postmenopausal EC cases. We also examined the associations between steroid hormones and EC status by including 110 healthy postmenopausal women. Steroid concentrations were analyzed in relation to clinicopathological features, recurrence and overall survival (OS). The mean follow-up time was 65.5 months and 26 patients experienced relapse after surgery for a recurrence incidence of 10.6% (6.4% Type I and 29.5% Type II). Recurrence and OS were related to a more aggressive disease but not linked to body mass index. Preoperative levels of estriol (E3) and estrone-sulfate (E1-S) were inversely associated with recurrence in a multivariate logistic regression analysis (Hazard ratios (HRs) of 0.31, P=0.039 and 3.01, P=0.024; respectively). All circulating steroids declined considerably after surgery almost reaching those of healthy women, except 4-methoxy-E2 (4MeO-E2) for which postoperative levels increased by 35% and were associated to a 68% decreased risk of recurrence (HR=0.32, P=0.015). Women diagnosed with both histological types of EC present significantly higher levels of steroids, in support of their mitogenic effects. The estrogen precursor E1-S, the anticancer metabolite 4MeO-E2, and E3 that exert mixed antagonist and agonist estrogenic activities and immunological effects, are potential independent prognostic factors.

PMID: 29092787 [PubMed - indexed for MEDLINE]

Sex modulates hepatic mitochondrial adaptations to high fat diet and physical activity.

Am J Physiol Endocrinol Metab. 2019 Apr 30;:

Authors: McCoin CS, Von Schulze A, Allen J, Fuller KN, Xia Q, Koestler DC, Houchen CJ, Maurer A, Dorn Ii GW, Shankar K, Morris EM, Thyfault JP

Abstract
The impact of sexual dimorphism and mitophagy on hepatic mitochondrial adaptations during the treatment of steatosis with physical activity are largely unknown. Here, we tested if deficiencies in liver-specific PGC-1a, a transcriptional co-activator of biogenesis, and BNIP3, a mitophagy regulator, would impact hepatic mitochondrial adaptations (respiratory capacity, H2O2 production, mitophagy) to a high-fat diet (HFD) and HFD plus physical activity via voluntary wheel running (VWR) in both sexes. Male and female wild type (WT), liver-specific PGC-1a heterozygote (LPGC-1a) and BNIP3 null mice were thermoneutral housed (29-31°C) and divided into three groups: sedentary - low fat diet (LFD), 16 weeks of (HFD), or 16 weeks of HFD with VWR for the final 8 weeks (HFD+VWR) (n=5-7/sex/group). HFD did not impair mitochondrial respiratory capacity or coupling in any group, however HFD+VWR significantly increased maximal respiratory capacity only in WT and PGC-1a females. Males required VWR to elicit mitochondrial adaptations that were inherently present in sedentary females including greater mitochondrial coupling efficiency and reduced H2O2 production. Females had overall reduced markers of mitophagy, steatosis, and liver damage. Steatosis and markers of liver injury were present in sedentary male mice on the HFD and were effectively reduced with VWR despite no resolution of steatosis. Overall, reductions in PGC-1a and loss of BNIP3 only modestly impacted mitochondrial adaptations to HFD and HFD+VWR with the biggest effect seen in BNIP3 females. In conclusion, hepatic mitochondrial adaptations to HFD and treatment of HFD-induced steatosis with VWR are more dependent on sex than PGC-1a or BNIP3.

PMID: 31039007 [PubMed - as supplied by publisher]

Activation of Pregnane X Receptor Sensitizes Mice to Hemorrhagic Shock Induced Liver Injury.

Hepatology. 2019 Apr 30;:

Authors: Xie Y, Xu M, Deng M, Li Z, Wang P, Ren S, Guo Y, Ma X, Fan J, Billiar TR, Xie W

Abstract
Hemorrhagic shock (HS) is a life-threatening condition associated with tissue hypoperfusion, and often leads to injury of multiple organs including the liver. Pregnane X receptor (PXR) is a species-specific xenobiotic receptor that regulates the expression of drug-metabolizing enzymes (DMEs) such as the cytochrome P450 3A (CYP3A). Many clinical drugs, including those often prescribed to trauma patients, are known to activate PXR and induce CYP3A. The goal of this study is to determine whether PXR plays a role in the regulation of DMEs in the setting of HS, and whether activation of PXR is beneficial or detrimental to HS-induced hepatic injury. PXR transgenic, knockout, and humanized mice were subject to HS, and the liver injury was assessed histologically and biochemically. The expression and/or activity of PXR and CYP3A were manipulated genetically or pharmacologically in order to determine their effects on HS-induced liver injury. Our results showed that genetic or pharmacological activation of PXR sensitized wild-type and hPXR/CYP3A4 humanized mice to HS-induced hepatic injury, whereas knockout of PXR protected mice from HS-induced liver injury. Mechanistically, the sensitizing effect of PXR activation was accounted for by PXR-responsive induction of CYP3A and increased oxidative stress in the liver. The sensitizing effect of PXR was attenuated by ablation or pharmacological inhibition of CYP3A, treatment with the antioxidant N-acetylcysteine amide (NACA), or treatment with a PXR antagonist. CONCLUSIONS: We have uncovered a novel function of PXR in HS-induced hepatic injury. Our results suggest that the unavoidable use of PXR-activating drugs in trauma patients has the potential to exacerbate HS-induced hepatic injury, which can be mitigated by the co-administration of anti-oxidative agents, CYP3A inhibitors, or PXR antagonists. This article is protected by copyright. All rights reserved.

PMID: 31038762 [PubMed - as supplied by publisher]