Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 26

Publication Record

Connections

Intersection of the Roles of Cytochrome P450 Enzymes with Xenobiotic and Endogenous Substrates: Relevance to Toxicity and Drug Interactions.
Guengerich FP
(2017) Chem Res Toxicol 30: 2-12
MeSH Terms: Animals, Cytochrome P-450 Enzyme System, Drug Interactions, Humans, Pharmaceutical Preparations, Xenobiotics
Show Abstract · Added March 14, 2018
Today much is known about cytochrome P450 (P450) enzymes and their catalytic specificity, but the range of reactions catalyzed by each still continues to surprise. Historically, P450s had been considered to be involved in either the metabolism of xenobiotics or endogenous chemicals, in the former case playing a generally protective role and in the latter case a defined physiological role. However, the line of demarcation is sometimes blurred. It is difficult to be completely specific in drug design, and some P450s involved in the metabolism of steroids and vitamins can be off-targets. In a number of cases, drugs have been developed that act on some of those P450s as primary targets, e.g., steroid aromatase inhibitors. Several of the P450s involved in the metabolism of endogenous substrates are less specific than once thought and oxidize several related structures. Some of the P450s that primarily oxidize endogenous chemicals have been shown to oxidize xenobiotic chemicals, even in a bioactivation mode.
0 Communities
1 Members
0 Resources
6 MeSH Terms
Survey of Human Oxidoreductases and Cytochrome P450 Enzymes Involved in the Metabolism of Xenobiotic and Natural Chemicals.
Rendic S, Guengerich FP
(2015) Chem Res Toxicol 28: 38-42
MeSH Terms: Biotransformation, Humans, Oxidoreductases, Xenobiotics
Show Abstract · Added January 20, 2015
Analyzing the literature resources used in our previous reports, we calculated the fractions of the oxidoreductase enzymes FMO (microsomal flavin-containing monooxygenase), AKR (aldo-keto reductase), MAO (monoamine oxidase), and cytochrome P450 participating in metabolic reactions. The calculations show that the fractions of P450s involved in the metabolism of all chemicals (general chemicals, natural, and physiological compounds, and drugs) are rather consistent in the findings that >90% of enzymatic reactions are catalyzed by P450s. Regarding drug metabolism, three-fourths of the human P450 reactions can be accounted for by a set of five P450s: 1A2, 2C9, 2C19, 2D6, and 3A4, and the largest fraction of the P450 reactions is catalyzed by P450 3A enzymes. P450 3A4 participation in metabolic reactions of drugs varied from 13% for general chemicals to 27% for drugs.
0 Communities
1 Members
0 Resources
4 MeSH Terms
Streptomyces cytochromes P450: applications in drug metabolism.
Lamb DC, Waterman MR, Zhao B
(2013) Expert Opin Drug Metab Toxicol 9: 1279-94
MeSH Terms: Biotransformation, Cytochrome P-450 Enzyme System, Drug Evaluation, Preclinical, Drug-Related Side Effects and Adverse Reactions, Genomics, Humans, Inactivation, Metabolic, Streptomyces, Xenobiotics
Show Abstract · Added March 7, 2014
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.
0 Communities
1 Members
0 Resources
9 MeSH Terms
Variation in xenobiotic transport and metabolism genes, household chemical exposures, and risk of childhood acute lymphoblastic leukemia.
Chokkalingam AP, Metayer C, Scelo GA, Chang JS, Urayama KY, Aldrich MC, Guha N, Hansen HM, Dahl GV, Barcellos LF, Wiencke JK, Wiemels JL, Buffler PA
(2012) Cancer Causes Control 23: 1367-75
MeSH Terms: Adolescent, Biological Transport, California, Case-Control Studies, Child, Child, Preschool, Environmental Exposure, Female, Genotype, Humans, Infant, Infant, Newborn, Male, Pesticides, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Risk Factors, Xenobiotics
Show Abstract · Added February 26, 2014
BACKGROUND - Recent studies suggest that environmental exposures to pesticides, tobacco, and other xenobiotic chemicals may increase risk of childhood acute lymphoblastic leukemia (ALL). We sought to evaluate the role of genes involved in xenobiotic transport and metabolism in childhood ALL risk, both alone and in conjunction with household chemical exposures previously found to be associated with childhood ALL risk.
METHODS - We conducted a population-based epidemiologic study of 377 cases and 448 controls in California, utilizing a haplotype-based approach to evaluate 42 xenobiotic transport and metabolism genes in conjunction with data on self-reported household chemical exposures.
RESULTS - We identified significant associations of childhood ALL risk with haplotypes of ABCB1, ARNT, CYP2C8, CYP1A2, CYP1B1, and IDH1. In addition, certain haplotypes showed significant joint effects with self-reported household chemical exposures on risk of childhood ALL. Specifically, elevated risks associated with use of paints in the home (ever) and indoor insecticides (pre-birth) were limited to subjects carrying specific haplotypes of CYP2C8 and ABCB1, respectively.
CONCLUSIONS - Our results provide support for a role of xenobiotic transport and metabolism pathways in risk of childhood ALL and indicate that genes in these pathways may modulate the risk of disease associated with use of common household chemicals. Additional studies are needed to confirm these findings and localize specific causal variants.
0 Communities
1 Members
0 Resources
17 MeSH Terms
Transcriptional ontogeny of the developing liver.
Lee JS, Ward WO, Knapp G, Ren H, Vallanat B, Abbott B, Ho K, Karp SJ, Corton JC
(2012) BMC Genomics 13: 33
MeSH Terms: Animals, Cluster Analysis, Erythroid Cells, Female, Fetus, Gene Expression Profiling, Gene Expression Regulation, Developmental, Hematopoietic Stem Cells, Humans, Liver, Male, Mice, Mice, Inbred C57BL, Nerve Tissue Proteins, Organ Specificity, Pancreas, Polypyrimidine Tract-Binding Protein, Pregnancy, Ribonucleoproteins, Transcription, Genetic, Wnt Signaling Pathway, Xenobiotics
Show Abstract · Added May 22, 2014
BACKGROUND - During embryogenesis the liver is derived from endodermal cells lining the digestive tract. These endodermal progenitor cells contribute to forming the parenchyma of a number of organs including the liver and pancreas. Early in organogenesis the fetal liver is populated by hematopoietic stem cells, the source for a number of blood cells including nucleated erythrocytes. A comprehensive analysis of the transcriptional changes that occur during the early stages of development to adulthood in the liver was carried out.
RESULTS - We characterized gene expression changes in the developing mouse liver at gestational days (GD) 11.5, 12.5, 13.5, 14.5, 16.5, and 19 and in the neonate (postnatal day (PND) 7 and 32) compared to that in the adult liver (PND67) using full-genome microarrays. The fetal liver, and to a lesser extent the neonatal liver, exhibited dramatic differences in gene expression compared to adults. Canonical pathway analysis of the fetal liver signature demonstrated increases in functions important in cell replication and DNA fidelity whereas most metabolic pathways of intermediary metabolism were under expressed. Comparison of the dataset to a number of previously published microarray datasets revealed 1) a striking similarity between the fetal liver and that of the pancreas in both mice and humans, 2) a nucleated erythrocyte signature in the fetus and 3) under expression of most xenobiotic metabolism genes throughout development, with the exception of a number of transporters associated with either hematopoietic cells or cell proliferation in hepatocytes.
CONCLUSIONS - Overall, these findings reveal the complexity of gene expression changes during liver development and maturation, and provide a foundation to predict responses to chemical and drug exposure as a function of early life-stages.
0 Communities
1 Members
0 Resources
22 MeSH Terms
Increased age reduces DAF-16 and SKN-1 signaling and the hormetic response of Caenorhabditis elegans to the xenobiotic juglone.
Przybysz AJ, Choe KP, Roberts LJ, Strange K
(2009) Mech Ageing Dev 130: 357-69
MeSH Terms: Adaptation, Physiological, Age Factors, Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Cytoprotection, DNA-Binding Proteins, Dose-Response Relationship, Drug, Down-Regulation, Forkhead Transcription Factors, Gene Expression Profiling, Mutation, Naphthoquinones, Oligonucleotide Array Sequence Analysis, Oxidative Stress, RNA Interference, Signal Transduction, Transcription Factors, Transcriptional Activation, Xenobiotics
Show Abstract · Added December 10, 2013
Cells adapt to stressors by activating mechanisms that repair damage and protect them from further injury. Stress-induced damage accumulates with age and contributes to age associated diseases. Increased age attenuates the ability to mount a stress response, but little is known about the mechanisms by which this occurs. To begin addressing this problem, we studied hormesis in the nematode Caenorhabditis elegans. When exposed to a low concentration of the xenobiotic juglone, young worms mount a robust hormetic stress response and survive a subsequent exposure to a higher concentration of juglone that is normally lethal to naïve animals. Old worms are unable to mount this adaptive response. Microarray and RNAi analyses demonstrate that an altered transcriptional response to juglone is responsible in part for the reduced adaptation of old worms. Many genes differentially regulated in young versus old animals are known or postulated to be regulated by the FOXO homologue DAF-16 and the Nrf2 homologue SKN-1. Activation of these pathways is greatly reduced in juglone stressed old worms. DAF-16- and SKN-1-like transcription factors play highly conserved roles in regulating stress resistance and longevity genes. Our studies provide a foundation for developing a molecular understanding of how age affects cytoprotective transcriptional pathways.
0 Communities
1 Members
0 Resources
20 MeSH Terms
Protein damage by reactive electrophiles: targets and consequences.
Liebler DC
(2008) Chem Res Toxicol 21: 117-28
MeSH Terms: Animals, Electrophoresis, Polyacrylamide Gel, Humans, Immunochemistry, Proteins, Proteomics, Signal Transduction, Xenobiotics
Show Abstract · Added March 20, 2014
It has been 60 years since the Millers first described the covalent binding of carcinogens to tissue proteins. Protein covalent binding was gradually overshadowed by the emergence of DNA adduct formation as the dominant paradigm in chemical carcinogenesis but re-emerged in the early 1970s as a critical mechanism of drug and chemical toxicity. Technology limitations hampered the characterization of protein adducts until the emergence of mass spectrometry-based proteomics in the late 1990s. The time since then has seen rapid progress in the characterization of the protein targets of electrophiles and the consequences of protein damage. Recent integration of novel affinity chemistries for electrophile probes, shotgun proteomics methods, and systems modeling tools has led to the identification of hundreds of protein targets of electrophiles in mammalian systems. The technology now exists to map the targets of damage to critical components of signaling pathways and metabolic networks and to understand mechanisms of damage at a systems level. The implementation of sensitive, specific analyses for protein adducts from both xenobiotic-derived and endogenous electrophiles offers a means to link protein damage to clinically relevant health effects of both chemical exposures and disease processes.
0 Communities
1 Members
0 Resources
8 MeSH Terms
Inter-individual variation of cytochrome P4502J2 expression and catalytic activities in liver microsomes from Japanese and Caucasian populations.
Yamazaki H, Okayama A, Imai N, Guengerich FP, Shimizu M
(2006) Xenobiotica 36: 1201-9
MeSH Terms: Adolescent, Adult, Aged, Alleles, Asian Continental Ancestry Group, Child, Child, Preschool, Cytochrome P-450 Enzyme System, European Continental Ancestry Group, Female, Gene Expression, Genotype, Humans, In Vitro Techniques, Japan, Male, Microsomes, Liver, Middle Aged, Oxidation-Reduction, Oxygenases, Xenobiotics
Show Abstract · Added March 26, 2014
The aim of this study was to investigate the inter-individual variations in cytochrome P4502J2 (CYP2J2) and its typical drug oxidation activities in human liver microsomes in both Japanese and Caucasian populations. CYP2J2 contents were determined immunochemically in liver microsomes from 20 Japanese and 29 Caucasian samples using recombinant CYP2J2 commercially available as a standard. Ebastine hydroxylation and astemizole O-demethylation activities were compared. The CYP2J2 genotype was determined by direct sequencing of liver genomic DNA. The mean expression levels of CYP2J2 determined immunochemically in liver microsomes from Japanese and Caucasian samples were 2.0 +/- 1.5 and 1.2 +/- 2.1 pmol CYP2J2 mg-1 protein (mean +/- standard deviation), respectively, accounting for 1.8 +/- 1.1% and 0.52 +/- 0.65% of the total hepatic P450 content (0.15 +/- 0.19 and 0.27 +/- 0.14 nmol P450 mg-1 protein, respectively). The individual variation of the two marker drug oxidation activities could not be fully accounted for by the CYP2J2 contents or currently known CYP2J2 genotypes. The amounts of CYP2J2 in liver microsomes with the CYP2J2*7 allele (-76G>T) were decreased to 39% compared with those of liver microsomes from other individuals. The results indicate that CYP2J2 accounts for approximately 1-2% of total P450 in human liver microsomes. The information about large inter-individual variation of the CYP2J2 suggests that this enzyme plays a significant role in the metabolism of xenobiotics and may be useful in in-silico simulations of drug disposition.
0 Communities
1 Members
0 Resources
21 MeSH Terms
The poisons within: application of toxicity mechanisms to fundamental disease processes.
Liebler DC
(2006) Chem Res Toxicol 19: 610-3
MeSH Terms: Atherosclerosis, Drug-Related Side Effects and Adverse Reactions, Humans, Metabolic Syndrome, Neurodegenerative Diseases, Oxidants, Oxidative Stress, Toxicology, Xenobiotics
Added March 20, 2014
0 Communities
1 Members
0 Resources
9 MeSH Terms
Life and times in biochemical toxicology.
Guengerich FP
(2005) Int J Toxicol 24: 5-21
MeSH Terms: Animals, Biochemistry, History, 19th Century, History, 20th Century, History, 21st Century, Humans, Toxicology, Xenobiotics
Show Abstract · Added March 5, 2014
The biochemical facets of toxicology have always had a major role in providing insight into mechanisms. Some of the history of the development of this area is summarized, including metabolism, enzymology, and the chemistry of reactive intermediates. Knowledge in these fields has had a major impact in the areas of drug metabolism and safety assessment, which are both critical steps in the development of pharmaceuticals and the rational use of commodity chemicals. The science of toxicology has developed considerably with input from other disciplines and today is poised to emerge as a predictive science with even more dramatic impact. The challenges ahead are considerable but there is renewed excitement in the potential of the field. As in the past, further advances in the field of toxicology will require the input of knowledge from many disciplines.
0 Communities
1 Members
0 Resources
8 MeSH Terms