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The accelerated metabolic demands of the working muscle cannot be met without a robust response from the liver. If not for the hepatic response, sustained exercise would be impossible. The liver stores, releases, and recycles potential energy. Exercise would result in hypoglycemia if it were not for the accelerated release of energy as glucose. The energetic demands on the liver are largely met by increased oxidation of fatty acids mobilized from adipose tissue. Adaptations immediately following exercise facilitate the replenishment of glycogen stores. Pancreatic glucagon and insulin responses orchestrate the hepatic response during and immediately following exercise. Like skeletal muscle and other physiological systems, liver adapts to repeated demands of exercise by increasing its capacity to produce energy by oxidizing fat. The ability of regular physical activity to increase fat oxidation is protective and can reverse fatty liver disease. Engaging in regular physical exercise has broad ranging positive health implications including those that improve the metabolic health of the liver.
© 2015 Elsevier Inc. All rights reserved.
INTRODUCTION - The biotransformation of drugs is critical in assessing safety and efficacy prior to human use. Cytochrome P450 (CYP; P450) enzymes are major enzymes involved in drug metabolism and bioactivation. In general, animal model systems are widely used to evaluate drug candidate toxicity and metabolism. Streptomyces strains have also been used for the metabolism of drugs screening prior to use in human medicine.
AREAS COVERED - Utilizing Streptomyces P450s uncovered by genomics to generate drug metabolites represents an additional practical means of new drug screening approach. Now, in the first such review since the advent of the post-genomic era, the authors provide an update on the present knowledge concerning the application of the Streptomyces species and associated P450s with their role(s) in drug metabolism.
EXPERT OPINION - Currently traditional biochemical methodology, such as chemical screening to identify substrates using purified enzymes, is still required for successful drug development. Nevertheless, the ability of the Streptomyces species, and their associated P450 enzymes, has shown promise for drug development because of their ability to mimic human drug-metabolizing P450. Furthermore, it should be pointed out that the metabolism of drug candidates with Streptomyces P450 may present a generation of novel products with totally different pharmacology with improved efficacy and pharmacokinetic profile.
Cytochrome P450 enzymes have major roles in the metabolism of steroids, drugs, carcinogens, eicosanoids, and numerous other chemicals. The P450s are collectively considered the most diverse catalysts known in biochemistry, although they operate from a basic structural fold and catalytic mechanism. The four minireviews in this thematic series deal with the unusual aspects of catalytic reactions and electron transfer pathway organization, the structural diversity of P450s, and the expanding roles of P450s in disease and medicine.
Acute kidney injury (AKI) is a common problem in hospitalized patients and is associated with significant morbidity and mortality. Two large trials showed no benefit from increased doses of renal replacement therapy (RRT) despite previous clinical data suggesting that increased clearance from RRT has beneficial effects. Since infection is the leading cause of death in AKI, my group and others hypothesized that increased RRT antibiotic clearance might create a competing morbidity. The data from my group, as well as those of other groups, show that many patients are underdosed when routine "1 size fits all" antibiotic dosing is used in patients with AKI receiving continuous RRT (CRRT). Here, concepts of drug distribution and clearance in AKI are briefly discussed and then 1 antibiotic (piperacillin) is discussed in depth to illustrate the challenges in applying the medical literature to clinical practice. The fact that published data on drug dosing in AKI and dialysis reflect the evolution of practice patterns and often do not apply to present prescribing habits is also discussed. A more general approach to drug dosing facilitates situation-specific prescribing by the nephrologist and critical care specialist.
Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
Considerable support exists for the roles of metabolism in modulating the carcinogenic properties of chemicals. In particular, many of these compounds are pro-carcinogens that require activation to electrophilic forms to exert genotoxic effects. We systematically analyzed the existing literature on the metabolism of carcinogens by human enzymes, which has been developed largely in the past 25 years. The metabolism and especially bioactivation of carcinogens are dominated by cytochrome P450 enzymes (66% of bioactivations). Within this group, six P450s--1A1, 1A2, 1B1, 2A6, 2E1, and 3A4--accounted for 77% of the P450 activation reactions. The roles of these P450s can be compared with those estimated for drug metabolism and should be considered in issues involving enzyme induction, chemoprevention, molecular epidemiology, interindividual variations, and risk assessment.
OBJECTIVE - The goal of pharmacogenomics is the translation of genomic discoveries into individualized patient care. Recent advances in the means to survey human genetic variation are fundamentally transforming our understanding of the genetic basis of interindividual variation in therapeutic response. The goal of this study was to systematically evaluate high-throughput genotyping technologies for their ability to assay variation in pharmacogenetically important genes (pharmacogenes). These platforms are either being proposed for or are already being widely used for clinical implementation; therefore, knowledge of coverage of pharmacogenes on these platforms would serve to better evaluate current or proposed pharmacogenetic association studies.
METHOD - Among the genes included in our study are drug-metabolizing enzymes, transporters, receptors, and drug targets, of interest to the entire pharmacogenetic community. We considered absolute and linkage disequilibrium (LD)-informed coverage, minor allele frequency spectrum, and functional annotation for a Caucasian population. We also examined the effect of LD, effect size, and cohort size on the power to detect single nucleotide polymorphism associations.
RESULTS - In our analysis of 253 pharmacogenes, we found that no platform showed more than 85% coverage of these genes (after accounting for LD). Furthermore, the lack of coverage showed a marked increase at minor allele frequencies of less than 20%. Even after accounting for LD, only 30% of the missense polymorphisms (which are enriched for low-frequency alleles) were covered by HapMap, with still lower coverage on the other platforms.
CONCLUSION - We have conducted the first systematic evaluation of the Axiom Genomic Database, Omni 2.5 M, and the Drug Metabolizing Enzymes and Transporters chip. This study is the first to utilize the 1000 Genomes Project to present a comprehensive evaluative framework. Our results provide a much-needed assessment of microarray-based genotyping and next-generation sequencing technologies' ability to survey fully the variation in genes of particular interest to the pharmacogenetics community. Our findings demonstrate the limitations of genome-wide methods and the challenges of implementing pharmacogenomic tests into the clinical context.
A reduction in endogenously generated reactive oxygen species in vivo delays benzo(a)pyrene (BaP)-accelerated atherosclerosis, as revealed in hypercholesterolemic mice overexpressing Cu/Zn-superoxide dismutase (SOD) and/or catalase. To understand the molecular events involved in this protective action, we studied the effects of Cu/Zn-SOD and/or catalase overexpression on BaP detoxification and on aryl hydrocarbon receptor (AhR) expression and its target gene expression in mouse aortic endothelial cells (MAECs). Our data demonstrate that overexpression of Cu/Zn-SOD and/or catalase leads to an 18- to 20-fold increase in the expression of AhR protein in MAECs. After BaP exposure, the amount of AhR binding to the cytochrome P450 (CYP) 1A1 promoter was significantly greater, and the concentrations of BaP reactive intermediates were significantly less in MAECs overexpressing Cu/Zn-SOD and/or catalase than in wild-type cells. In addition, the BaP-induced CYP1A1 and 1B1 protein levels and BaP-elevated glutathione S-transferase (GST) activity were significantly higher in these transgenic cells, in parallel with elevated GSTp1, CYP1A1, and CYP1B1 mRNA levels, compared to wild-type MAECs. Moreover, knockdown of AhR with RNA interference diminished the Cu/Zn-SOD and catalase enhancement of CYP1A1 expression, GST activity, and BaP detoxification. These data demonstrate that overexpression of Cu/Zn-SOD and/or catalase is associated with upregulation of AhR and its target genes, such as xenobiotic-metabolizing enzymes.
Breast cancer resistance protein (BCRP) is an efflux transporter expressed in tissues that act as barriers to drug entry. Given that single nucleotide polymorphisms (SNPs) in the ABCG2 gene encoding BCRP are common, the possibility exists that these genetic variants may be a determinant of interindividual variability in drug response. The objective of this study is to confirm the human BCRP-mediated transport of sulfasalazine in vitro, evaluate interindividual variation in BCRP expression in human intestine and to determine the role of ABCG2 SNPs to drug disposition in healthy patients using sulfasalazine as a novel in vivo probe. To evaluate these objectives, pinch biopsies were obtained from 18 patients undergoing esophagogastro-duodenoscopy or colonoscopy for determination of BCRP expression in relation to genotype. Wild-type and variant BCRP were expressed in a heterologous expression system to evaluate the effect of SNPs on cell-surface trafficking. A total of 17 healthy individuals participated in a clinical investigation to determine the effect of BCRP SNPs on sulfasalazine pharmacokinetics. In vitro, the cell surface protein expression of the common BCRP 421 C>A variant was reduced in comparison with the wild-type control. Intestinal biopsy samples revealed that BCRP protein and mRNA expression did not significantly differ between patients with 34GG/421CC versus patients with 34GG/421CA genotypes. Remarkably, in subjects with 34GG/421CA genotype, sulfasalazine area under the concentration-time curve was 2.4-fold greater compared with 34GG/421CC subjects (P<0.05). This study links commonly occurring SNPs in BCRP with significantly increased oral sulfasalazine plasma exposure in humans. Accordingly, sulfasalazine may prove to have utility as in vivo probe for assessing the clinical impact of BCRP for the disposition and efficacy of drugs.
The field of cytochrome P450 (P450) research has developed considerably over the past 20 years, and many important papers on the roles of P450s in chemical toxicology have appeared in Chemical Research in Toxicology. Today, our basic understanding of many of the human P450s is relatively well-established, in terms of the details of the individual genes, sequences, and basic catalytic mechanisms. Crystal structures of several of the major human P450s are now in hand. The animal P450s are still important in the context of metabolism and safety testing. Many well-defined examples exist for roles of P450s in decreasing the adverse effects of drugs through biotransformation, and an equally interesting field of investigation is the bioactivation of chemicals, including drugs. Unresolved problems include the characterization of the minor "orphan" P450s, ligand cooperativity and kinetic complexity of several P450s, the prediction of metabolism, the overall contribution of bioactivation to drug idiosyncratic problems, the extrapolation of animal test results to humans in drug development, and the contribution of genetic variation in human P450s to cancer incidence.
This study provides evidence that in mammary epithelial cells the pluripotent cytokine TGF-beta1 repressed expression of multiple genes involved in Phase II detoxification. GCLC, the gene that encodes the catalytic subunit of the enzyme glutamate cysteine ligase, the rate-limiting enzyme in the biosynthesis of glutathione, was used as a molecular surrogate for investigating the mechanisms by which TGF-beta suppressed Phase II gene expression. TGF-beta was found to suppress luciferase reporter activity mediated by the human GCLC proximal promoter, as well as reporter activity mediated by the GCLC antioxidant response element, ARE4. TGF-beta downregulated expression of endogenous GCLC mRNA and GCLC protein. TGF-beta suppression of the Phase II genes correlated with a decrease in cellular glutathione and an increase in cellular reactive oxygen species. Ectopic expression of constitutively active Smad3E was sufficient to inhibit both reporters in the absence of TGF-beta, whereas dominant negative Smad3A blocked TGF-beta suppression. Smad3E suppressed Nrf2-mediated activation of the GCLC reporter. We demonstrate that TGF-beta increased ATF3 protein levels, as did transient overexpression of Smad3E. Ectopic expression of ATF3 was sufficient to suppress the GCLC reporter activity, as well as endogenous GCLC expression. These results demonstrate that Smad3-ATF3 signaling mediates TGF-beta repression of ARE-dependent Phase II gene expression and potentially provide critical insight into mechanisms underlying TGF-beta1 function in carcinogenesis, tissue repair, and fibrosis.