Relative Activation of Human Pregnane X Receptor versus Constitutive Androstane Receptor Defines Distinct Classes of CYP2B6 and CYP3A4 Inducers

Both the human pregnane X receptor (hPXR) and constitutive androstane receptor (hCAR) are capable of regulating CYP3A4 and CYP2B6 gene expression. However, the majority of currently identified CYP3A4 and CYP2B6 inducers are confirmed activators of hPXR but not hCAR. To compare these receptors with respect to their chemical selectivities, 16 drugs known to induce CYP3A4 and/or CYP2B expression were evaluated for relative activation of hPXR versus hCAR. Because of the high basal but low chemical-induced activation of hCAR in immortalized cells, alternative methods were used to evaluate hCAR activation potential. Thirteen of the 16 compounds were classified as moderate to strong hPXR activators. In contrast, carbamazepine (CMZ), efavirenz (EFV), and nevirapine (NVP) were classified as negligible or weak hPXR activators at concentrations associated with efficacious CYP2B6 reporter or endogenous gene induction in primary human hepatocytes, suggesting potential activation of hCAR. Subsequent experiments demonstrated that these three drugs efficiently induced nuclear accumulation of in vivo-transfected enhanced yellow fluorescent protein-hCAR and significantly increased expression of a CYP2B6 reporter gene when hCAR was expressed in CAR−/− mice. In addition, using a recently identified, chemically responsive splice variant of hCAR (hCAR3), the hCAR activation profiles of the 16 compounds were evaluated. By combining results from the hPXR- and hCAR3-based reporter gene assays, these inducers were classified as hPXR, hCAR, or hPXR/hCAR dual activators. Our results demonstrate that CMZ, EFV, and NVP induce CYP2B6 and CYP3A4 preferentially through hCAR and that hCAR3 represents a sensitive tool for in vitro prediction of chemical-mediated human CAR activation

EVALUATION OF THE CONTRIBUTION OF CYTOCHROME P450 3A4 TO HUMAN LIVER MICROSOMAL BUPROPION HYDROXYLATION

This paper is available online at http://dmd.aspetjournals.org ABSTRACT: The purpose of this investigation was to evaluate the role of cytochrome P450 (CYP) 3A4 in human liver microsomal bupropion (BUP) hydroxylation. Across the BUP concentration range of 0.075 to 12 mM, cDNA-expressed CYP3A4 demonstrated BUP hydroxylase activity only when incubated with concentrations >4 mM. When assayed at 12 mM BUP, cDNA-expressed CYP3A4 catalyzed BUP hydroxylation at a 30-fold lower rate than cDNA-expressed CYP2B6 (0.2 versus 7 pmol/min/pmol of P450 Bupropion (BUP) 1 is a second-generation antidepressant agent that is also used in the management of smoking cessation. This drug undergoes extensive hepatic metabolism in humans via oxidative and reductive pathways Clinical pharmacokinetic studies have demonstrated 3-to 10-fold interindividual differences in HBUP C max and AUC In a prior in vitro study reported in abstract form, CYP3A4 demonstrated the second highest rate of BUP hydroxylation among a panel of cDNA-expressed P450 isozyme

Author Impact Metrics in Communication Sciences and Disorder Research

Purpose: The purpose was to examine author-level impact metrics for faculty in the communication sciences and disorder research field across a variety of databases. Method: Author-level impact metrics were collected for faculty from 257 accredited universities in the United States and Canada. Three databases (i.e., Google Scholar, ResearchGate, and Scopus) were utilized. Results: Faculty expertise was in audiology (24.4%; n = 490) and speech-language pathology (75.6%; n = 1,520). Women comprised 68.1% of faculty, and men comprised 31.9% of faculty. The percentage of faculty in the field of communication sciences and disorders identified in each database was 10.5% (n = 212), 44.0% (n = 885), and 84.4% (n = 1,696) for Google Scholar, ResearchGate, and Scopus, respectively. In general, author-level impact metrics were positively skewed. Metric values increased significantly with increasing academic rank (p < .05), were greater for men versus women (p < .05), and were greater for those in audiology versus speech-language pathology (p < .05). There were statistically significant positive correlations between all author-level metrics (p < .01). Conclusions: These author-level metrics may serve as a benchmark for scholarly production of those in the field of communication sciences and disorders and may assist with professional identity management, tenure and promotion review, grant applications, and employment

Intergenerational Transmission of Glucose Intolerance and Obesity by In Utero Undernutrition in Mice

OBJECTIVE—Low birth weight (LBW) is associated with increased risk of obesity, diabetes, and cardiovascular disease during adult life. Moreover, this programmed disease risk can progress to subsequent generations. We previously described a mouse model of LBW, produced by maternal caloric undernutrition (UN) during late gestation. LBW offspring (F1-UN generation) develop progressive obesity and impaired glucose tolerance (IGT) with aging. We aimed to determine whether such metabolic phenotypes can be transmitted to subsequent generations in an experimental model, even in the absence of altered nutrition during the second pregnancy

Pharmacogenetic & Pharmacokinetic Biomarker for Efavirenz Based ARV and Rifampicin Based Anti-TB Drug Induced Liver Injury in TB-HIV Infected Patients

BACKGROUND: Implication of pharmacogenetic variations and efavirenz pharmacokinetics in concomitant efavirenz based antiviral therapy and anti-tubercular drug induced liver injury (DILI) has not been yet studied. We performed a prospective case-control association study to identify the incidence, pharmacogenetic, pharmacokinetic and biochemical predictors for anti-tubercular and antiretroviral drugs induced liver injury (DILI) in HIV and tuberculosis (TB) co-infected patients. METHODS AND FINDINGS: Newly diagnosed treatment naïve TB-HIV co-infected patients (n = 353) were enrolled to receive efavirenz based ART and rifampicin based anti-TB therapy, and assessed clinically and biochemically for DILI up to 56 weeks. Quantification of plasma efavirenz and 8-hydroxyefaviernz levels and genotyping for NAT2, CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 genes were done. The incidence of DILI and identification of predictors was evaluated using survival analysis and the Cox Proportional Hazards Model. The incidence of DILI was 30.0%, or 14.5 per 1000 person-week, and that of severe was 18.4%, or 7.49 per 1000 person-week. A statistically significant association of DILI with being of the female sex (p = 0.001), higher plasma efavirenz level (p = 0.009), efavirenz/8-hydroxyefavirenz ratio (p = 0.036), baseline AST (p = 0.022), ALT (p = 0.014), lower hemoglobin (p = 0.008), and serum albumin (p = 0.007), NAT2 slow-acetylator genotype (p = 0.039) and ABCB1 3435TT genotype (p = 0.001). CONCLUSION: We report high incidence of anti-tubercular and antiretroviral DILI in Ethiopian patients. Between patient variability in systemic efavirenz exposure and pharmacogenetic variations in NAT2, CYP2B6 and ABCB1 genes determines susceptibility to DILI in TB-HIV co-infected patients. Close monitoring of plasma efavirenz level and liver enzymes during early therapy and/or genotyping practice in HIV clinics is recommended for early identification of patients at risk of DILI

Smoking Cessation Pharmacogenetics: Analysis of Varenicline and Bupropion in Placebo-Controlled Clinical Trials

Despite effective therapies for smoking cessation, most smokers find quitting difficult and most successful quitters relapse. Considerable evidence supports a genetic risk for nicotine dependence; however, less is known about the pharmacogenetics of smoking cessation. In the first pharmacogenetic investigation of the efficacy of varenicline and bupropion, we examined whether genes important in the pharmacodynamics and pharmacokinetics of these drugs and nicotine predict medication efficacy and adverse events. Subjects participated in randomized, double-blind, placebo-controlled smoking cessation clinical trials, comparing varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, with bupropion, a norepinephrine/dopamine reuptake inhibitor, and placebo. Primary analysis included 1175 smokers of European ancestry, and 785 single nucleotide polymorphisms from 24 genes, representing 254 linkage disequilibrium (LD) bins (genes included nAChR subunits, additional varenicline-specific genes, and genes involved in nicotine or bupropion metabolism). For varenicline, continuous abstinence (weeks 9–12) was associated with multiple nAChR subunit genes (including CHRNB2, CHRNA5, and CHRNA4) (OR=1.76; 95% CI: 1.23–2.52) (p<0.005); for bupropion, abstinence was associated with CYP2B6 (OR=1.78; 95% CI: 1.27–2.50) (p<0.001). Incidence of nausea was associated with several nAChR subunit genes (OR=0.50; 95% CI: 0.36–0.70) (p<0.0001) and time to relapse after quitting was associated with HTR3B (HR=1.97; 95% CI: 1.45–2.68) (p<0.0001). These data provide evidence for multiple genetic loci contributing to smoking cessation and therapeutic response. Different loci are associated with varenicline vs bupropion response, suggesting that additional research may identify clinically useful markers to guide treatment decisions

Effectiveness of post-fire soil erosion mitigation treatments: a systematic review and meta-analysis

Wildfires are known to be one of the main causes of soil erosion and land degradation, and their impacts on ecosystems and society are expected to increase in the future due to changes in climate and land use. It is therefore vital to mitigate the increased hydrological and erosive response after wildfires to maintain the sustainability of ecosystems and protect the values at risk downstream from the fire-affected areas. Soil erosion mitigation treatments have been widely applied after wildfires but assessment of their effectiveness has been limited to local and regional-scale studies, whose conclusions may depend heavily on site-specific conditions. To overcome this limitation, a meta-analysis approach was applied to investigations of post-wildfire soil erosion mitigation treatments published in peer-reviewed journals. A meta-analysis database was compiled that consisted of 53 and 222 pairs of treated/untreated observations on post-fire runoff and erosion, respectively, extracted from 34 publications indexed in Scopus. The overall effectiveness of mitigation treatments, expressed as the quantitative metric ‘effect size’, was determined for both the runoff and erosion observations, and further analyzed for four different types of treatments (cover-based, barriers, seeding, and chemical treatments). The erosion observations involving cover-based treatments were analyzed for differences in effectiveness between 3 different types of mulch materials (straw, wood-based, and hydromulch) as well as between different application rates of straw and wood materials. Finally, the erosion observations were also analyzed for the overall effectiveness of post-fire year, burn severity, rainfall amount and erosivity, and ground cover. The meta-analysis results show that all four types of treatments significantly reduced post-fire soil erosion, but that only the cover and barrier treatments significantly reduced post-fire runoff. From the three different cover treatments, straw and wood mulches were significantly more effective in mitigating erosion than hydromulch. In addition, the effectiveness of both straw and wood mulches depended on their application rates. Straw mulching was less effective at rates below than above 200 g m−2, while mulching with wood materials at high rates (1300 to 1750 g m−2) produced more variable outcomes than lower rates. Results also suggest that the overall effectiveness of the treatments was greatest shortly after fire, in severely burned sites, providing or promoting the development of ground cover over 70%, and that it increased with increasing rainfall erosivity. It can be concluded that, in overall terms, the application of the studied post-fire erosion mitigation treatments represented a better choice than doing nothing, especially in sites where erosion is high. However, the meta-analysis highlights under-representation of studies on this topic outside of the USA, Spain and Portugal. It was also observed that most of the studies were conducted at hillslope scale and tested mulching (namely straw, wood and hydromulch) and/or barriers, while larger scales and other treatments were scarcely addressed. Further efforts need to be made in testing, from field and modeling studies, combinations of existing and/or emerging erosion mitigation treatments to ensure that the most adequate measures are applied after fires.publishe

Current Industrial Practices in Assessing CYP450 Enzyme Induction: Preclinical and Clinical

Induction of drug metabolizing enzymes, such as the cytochromes P450 (CYP) is known to cause drug-drug interactions due to increased elimination of co-administered drugs. This increased elimination may lead to significant reduction or complete loss of efficacy of the co-administered drug. Due to the significance of such drug interactions, many pharmaceutical companies employ screening and characterization models which predict CYP enzyme induction to avoid or attenuate the potential for drug interactions with new drug candidates. The most common mechanism of CYP induction is transcriptional gene activation. Activation is mediated by nuclear receptors, such as AhR, CAR, and PXR that function as transcription factors. Early high throughput screening models utilize these nuclear hormone receptors in ligand binding or cell-based transactivation/reporter assays. In addition, immortalized hepatocyte cell lines can be used to assess enzyme induction of specific drug metabolizing enzymes. Cultured primary human hepatocytes, the best established in vitro model for predicting enzyme induction and most accepted by regulatory agencies, is the predominant assay used to evaluate induction of a wide variety of drug metabolizing enzymes. These in vitro models are able to appropriately predict enzyme induction in patients when compared to clinical drug-drug interactions. Finally, transgenic animal models and the cynomolgus monkey have also been shown to recapitulate human enzyme induction and may be appropriate in vivo animal models for predicting human drug interactions