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PubMed2003

What is toxicology and how does toxicity occur?

Toxicology has matured since it was defined as the 'science of poisons'. Modern toxicology is no longer anthropocentric but takes on different views at various biological systems, including ecosystems. Each will interact specifically when exposed to defined chemical agents, including drugs. Adverse effects during drug therapy or after (accidental) poisoning are the result of some negative interactions between the agent and the exposed biological system. Toxicity is no longer a specific property of drugs and chemicals but an operative term to describe the adverse outcome of a specific drugs-host interaction. Newer developments in toxicology have focused on the host. Toxicogenetics continues to provide answers to variations of host response to xenobiotics, including drugs. Clinically relevant genetic polymorphisms and gene defects have been detected, and their number is rapidly growing. The key to understanding is in the host proteins that interact with the drug and mediate the cellular response. Hence, the proteom, i.e. the complete set of proteins of a cell, an individual or a species, determines how an exposed biological system may interact with the manifold of different xenobiotics. Structure-activity studies try to find out useful predictive parameters for risk and toxicity assessment.

Absorption↗

PubMedDate not supplied

Genetic variation and exposure related risk estimation: will toxicology enter a new era? DNA repair and cancer as a paradigm.

With the vast technological and informational resources increasingly available from investments in "genomics," toxicology and much of biological science, is faced with previously undreamed of opportunities and equally daunting challenges. The ability to generate the large quantities of data becoming routinely available could not be imagined a decade ago. The complexities of data analysis are increasingly the rate-limiting element in scientific advances. The expectations that these large scientific investments will reduce the incidence of human disease and improve health are very high. An emphasis on genetic variation and Toxicogenetics is expected to yield risk estimates for specific rather than average individuals and individuals with varied lifestyles and complex patterns of exposure. Examples from studies of polymorphic variation in DNA repair genes in the healthy population and cancer risk highlight the complexity and challenges of incorporating genetic variation into quantitative estimates of risk associated with environmentally relevant exposures. Similar issues exist in selecting the animal models most appropriate for predicting human risk from environmental exposures to toxic agents.

Animals↗

PubMed2003

Glucuronidation of 1'-hydroxyestragole (1'-HE) by human UDP-glucuronosyltransferases UGT2B7 and UGT1A9.

Estragole (4-allyl-1-methoxybenzene) is a naturally occurring food flavoring agent found in basil, fennel, bay leaves, and other spices. Estragole and its metabolite, 1'-hydroxyestragole (1'-HE), are hepatocarcinogens in rodent models. Recent studies from our laboratory have shown that glucuronidation of 1'-HE is a major detoxification pathway for estragole and 1'-HE, accounting for as much as 30% of urinary metabolites of estragole in rodents. Therefore, this study was designed to investigate the glucuronidation of 1'-HE in human liver microsomes in vitro and identify the specific uridine diphosphate glucuronosyltransferase (UGT) isoforms responsible for 1'-HE glucuronidation. The formation of the glucuronide of 1'-HE (1'-HEG) followed atypical kinetics, and the data best fit to a Hill equation, resulting in apparent kinetic parameters of Km = 1.45 mM, Vmax = 164.5 pmoles/min/mg protein, and n = 1.4. There was a significant intersubject variation in 1'-HE glucuronidation in 27 human liver samples, with a CV of 42%. A screen of cDNA expressed UGT isoforms indicated that UGT2B7 (83.94 +/- 0.188 pmols/min/mg), UGT1A9 (51.36 +/- 0.72 pmoles/min/mg), and UGT2B15 (8.18 +/- 0.037 pmoles/min/mg) were responsible for 1'-HEG formation. Glucuronidation of 1'-HE was not detected in cells expressing UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, and UGT1A10. 1'-HE glucuronidation in 27 individual human liver samples significantly (p < 0.05) correlated with the glucuronidation of other UGT2B7 substrates (morphine and ibuprofen). These results imply that concomitant chronic intake of therapeutic drugs and dietary components that are UGT2B7 and/or UGT1A9 substrates may interfere with estragole metabolism. Our results also have toxicogenetic significance, as UGT2B7 is polymorphic and could potentially result in genetic differences in glucuronidation of 1'-HE and, hence, toxicity of estragole.

Analgesics, Opioid↗

PubMed2006

The use of premature chromosome condensation to study in interphase cells the influence of environmental factors on human genetic material.

Nowadays, there is a constantly increasing concern regarding the mutagenic and carcinogenic potential of a variety of harmful environmental factors to which humans are exposed in their natural and anthropogenic environment. These factors exert their hazardous potential in humans' personal (diet, smoking, pharmaceuticals, cosmetics) and occupational environment that constitute part of the anthropogenic environment. It is well known that genetic damage due to these factors has dramatic implications for human health. Since most of the environmental genotoxic factors induce arrest or delay in cell cycle progression, the conventional analysis of chromosomes at metaphase may underestimate their genotoxic potential. Premature Chromosome Condensation (PCC) induced either by means of cell fusion or specific chemicals, enables the microscopic visualization of interphase chromosomes whose morphology depends on the cell cycle stage, as well as the analysis of structural and numerical aberrations at the G1 and G2 phases of the cell cycle. The PCC has been successfully used in problems involving cell cycle analysis, diagnosis and prognosis of human leukaemia, assessment of interphase chromosome malformations resulting from exposure to radiation or chemicals, as well as elucidation of the mechanisms underlying the conversion of DNA damage into chromosomal damage. In this report, particular emphasis is given to the advantages of the PCC methodology used as an alternative to conventional metaphase analysis in answering questions in the fields of radiobiology, biological dosimetry, toxicogenetics, clinical cytogenetics and experimental therapeutics.

Animals↗

PubMed2006

Pharmacogenetics, pharmacogenomics and ecogenetics.

Pharmacogenetics and pharmacogenomics deal with the role of genetic factors in drug effectiveness and adverse drug reactions. The promise of a personalized medicine is beginning to be explored but requires much more clinical and translational research. Specific DNA abnormalities in some cancers already have led to effective targeted treatments. Racially determined frequency differences in pharmacogenetic traits may affect choice of treatment requiring specific testing rather than basing treatments according to racial designation. The role of genes in variable responses to foreign chemicals (xenobiotics) has been termed ecogenetics or toxicogenetics raising problems in public health and occupational medicine. Nutrigenetics refers to genetic variation in response to nutrients and may affect nutritional requirements and predisposition to chronic disease.

DNA↗

PubMed2002

From pharmacogenetics and ecogenetics to pharmacogenomics.

The origin and development of pharmacogenetics are traced with emphasis on early hints by Garrod, Haldane, and later by RJ Williams. The field was delineated by Motulsky in 1957 and described as pharmacogenetics by Vogel in 1959. Kalow's monograph (1962) definitely established the discipline. Resemblance of identical twins in drug metabolism as compared with non identical twins (Vesell, 1970's) established the general importance of polygenic inheritance in disposal of many drugs. Ecogenetics was defined by Brewer in 1971 as dealing with genetic variation affecting the response to any environmental agents with emphasis on xenobiotics. More recent developments have broadened pharmacogenetic approaches to include novel genomic techniques with introduction of the term pharmacogenomics in the 1990's. Genetic and genomic approaches (toxicogenetics and toxicogenomics) are also being applied in the "environmental genome project". The interaction of genetic variation with dietary factors led to the field of Nutritional ecogenetics (Nutrigenomics) which relates the role of genetics to nutritional requirements and nutrition-mediated susceptibility to chronic disease. The total promise of pharmacogenomics is often overstated. The field is likely to have an impact on choice of drug therapy and avoidance of adverse events but is unlikely to lead to a revolution in therapeutics. Aspects of pharmacogenomic approaches and its applications including problems of premature commercialization are discussed.

Genetics↗

PubMed2004

Global gene expression analysis of human bronchial epithelial cells treated with tobacco condensates.

Gene expression patterns were assessed in normal human bronchial epithelial (NHBE) cells exposed to cigarette smoke condensates (CSC) from commercial cigarettes in order to develop a better understanding of the genomic impact of tobacco exposure, and to define biomarkers that can potentially discriminate tobacco-related effects and outcomes in a clinical setting. NHBE cells were treated with CSCs from two American brands for up to 12 hours in the presence of S9 microsomal fraction from Aroclor 1254-treated rats. High-density oligonucleotide microarrays coupled with a novel statistical analysis that relies on statistical significance levels rather than arbitrary fold-change differences was used to identify genes that undergo expression alterations upon treatment. Expression patterns of approximately 3700 genes were altered after CSC treatments. While a majority of these genes were affected by both CSCs, each condensate also affected a unique subset of approximately 1000 genes. An unexpected finding was that S9, required for metabolizing procarcinogens in CSCs to carcinogenic metabolites, also altered the expression of approximately 1700 genes. Exposure of NHBE cells to different CSCs alters the expression of a large set of genes that affect a common set of biological pathways including those relevant to carcinogenesis. Identification of CSC-affected genes and underlying biological processes may generate an atlas of molecular events that includes biomarkers of tobacco exposure and disease status in smokers. Finally, the finding that S9 affects the expression of a number of genes may have implications for various toxicogenetic assays currently used by regulatory agencies to evaluate harmful effects in exposed humans.

Adult↗

PubMed2004

[Genomic dosages of active rRNA genes in coke-oven workers].

Genomic dosage (copy number) of active ribosomal genes was evaluated using visual semi-quantitative method determining the sizes of Ag-NORs in acrocentric chromosomes after selective silver nitrate staining. A relationship between the length of service and the active ribosomal gene copy number was established: the highest numbers of active rRNA genes were observed in coke-oven workers with a length of service exceeding 20 years. An inverse relationship between the individual doses of active ribosomal genes and toxicogenetic susceptibility of the workers to the occupational factors was also revealed.

Adolescent↗

PubMedDate not supplied

[A modification factor of spontaneous chromosomal aberrations in miner's towns and settlements].

The level and qualitative spectrum of spontaneous chromosomal aberrations (CA) were comparatively analyzed in the lymphocytes of 655 children and adolescents from the Kemerovo Region. The presented sample was divided into 3 groups according to the type of an inhabited locality: 1) small miner's towns; 2) large industrial towns; and 3) rural localities. The maximum frequency of CA (3.77 +/- 0.22%) was noted in a group of dwellers in the miner's towns; its minimum frequency (2.68 +/- 0.17%) among the rural inhabitants. The significant clastogenic effects (including the markers of radiation exposure) were detected in the miner's towns located in the southern part of the region, which represented mountain and submountain areas. At the same time, in the northern and western parts of the Kemerovo Region, the average frequencies of CA in children and adolescents did not exceed the control background values. Thus, the residence in the inhabited localities specializing in mining is not a factor of absolute toxicogenetic risk.

Adolescent↗

PubMed1991

[Toxicologic estimation, an element of therapeutical progress].

The clinical toxicology plays a great part to the progresses of human therapy. It is an essential observation for a good clinical use of drugs and of materials used by physicians. It permits a better knowledge of the dose-effect relationship (in acute either in chronic adverse effects). It specifies the statement of the therapeutic efficacy between the threshold, a placebo effect with adverse disorders as those possibly related to any xenobiotic and the overdose where the nocivity predominates on the therapeutic results. A better detection of some individual responses as adverse or toxic reactions due to a genetic peculiarity belongs to clinical toxicogenetic studies in parallel with pharmacogenetics. The recent evolution of drugs needs a more scientific approach of the therapy for cytotoxic drugs largely used against cancers, in terms of tolerable doses, cumulative actions, interactions and cofactors. On the opposite, the bio-chemical variations of new bio-drugs acting as real bioprotheses of hormones or biomediators need specific toxicological studies according to the progresses and to the limits of biotechnologies. Among numerous drugs issued of chemical research one must separate the reversible functional drugs designed as enzyme-inhibitors or cellular receptors ligands very close to the dominant themes of biochemistry and experimental physiology from chemicals coined by synthetic "chance" which are for the time being plain xenobiotics whose dangers are often poorly evaluated but whose practical applications will take place either in disciplines related to pharmacopea like chemicals used in plant protection, either beginning their commercial trip very far from health concern in industrial preparations and being brought back to medicine as plastics, glues or metallic implants.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

[Influence of Rhizoma pinelliae on the occurrence of micronucleus in bone marrow polychromatic erythrocytes (PCE) in mice and frequencies of SCE in cultured human lymphocytes].

Contradictory effects of Rhizoma Pinelliae have been reported in pregnant mice, rats and rabbits, because the decoction of Rhizoma Pinelliae has obvious embryotoxicity. This paper was obtain an experimental analysis of the frequencies of micronucleus of bone marrow polychromatic erythrocytes (PCE) in mice and sister chromatid exchange (SCE) in cultural lymphocytes of human. The results showed that the decoction of Rhizoma Pinelliae neither induces the occurrencies of micronucleus nor SCE frequencies. Therefore, it may be concluded that the decoction does not have toxicogenetical effects.

Animals↗

PubMed1997

[Procedure for complex toxico-genetical investigations].

A biomonitoring system is proposed, which involves measurement of environmental genetoxicants, determination of mutagenic accumulation in biological substrates of human beings and the severity of genetic abnormalities in their somatic cells. The toxicogenetical monitoring system includes the assessment of the examinees mental status. The results of application of the system are given by using as an example two Yaroslavl (machine-building and oil-processing) plants.

Adult↗

PubMed2006

The Comparative Toxicogenomics Database (CTD): a resource for comparative toxicological studies.

The etiology of most chronic diseases involves interactions between environmental factors and genes that modulate important biological processes (Olden and Wilson, 2000. Nat Rev Genet 1(2):149-153). We are developing the publicly available Comparative Toxicogenomics Database (CTD) to promote understanding about the effects of environmental chemicals on human health. CTD identifies interactions between chemicals and genes and facilitates cross-species comparative studies of these genes. The use of diverse animal models and cross-species comparative sequence studies has been critical for understanding basic physiological mechanisms and gene and protein functions. Similarly, these approaches will be valuable for exploring the molecular mechanisms of action of environmental chemicals and the genetic basis of differential susceptibility.

Animals↗

PubMed2006

Predictive toxicogenomics approaches reveal underlying molecular mechanisms of nongenotoxic carcinogenicity.

Toxicogenomics technology defines toxicity gene expression signatures for early predictions and hypotheses generation for mechanistic studies, which are important approaches for evaluating toxicity of drug candidate compounds. A large gene expression database built using cDNA microarrays and liver samples treated with over one hundred paradigm compounds was mined to determine gene expression signatures for nongenotoxic carcinogens (NGTCs). Data were obtained from male rats treated for 24 h. Training/testing sets of 24 NGTCs and 28 noncarcinogens were used to select genes. A semiexhaustive, nonredundant gene selection algorithm yielded six genes (nuclear transport factor 2, NUTF2; progesterone receptor membrane component 1, Pgrmc1; liver uridine diphosphate glucuronyltransferase, phenobarbital-inducible form, UDPGTr2; metallothionein 1A, MT1A; suppressor of lin-12 homolog, Sel1h; and methionine adenosyltransferase 1, alpha, Mat1a), which identified NGTCs with 88.5% prediction accuracy estimated by cross-validation. This six genes signature set also predicted NGTCs with 84% accuracy when samples were hybridized to commercially available CodeLink oligo-based microarrays. To unveil molecular mechanisms of nongenotoxic carcinogenesis, 125 differentially expressed genes (P<0.01) were selected by Student's t-test. These genes appear biologically relevant, of 71 well-annotated genes from these 125 genes, 62 were overrepresented in five biochemical pathway networks (most linked to cancer), and all of these networks were linked by one gene, c-myc. Gene expression profiling at early time points accurately predicts NGTC potential of compounds, and the same data can be mined effectively for other toxicity signatures. Predictive genes confirm prior work and suggest pathways critical for early stages of carcinogenesis.

Animals↗

PubMed2004

Toxicogenomic difference between diethylstilbestrol and 17beta-estradiol in mouse testicular gene expression by neonatal exposure.

In this study, we investigated the effects of neonatal exposure to exogenous estrogen (diethylstilbestrol: DES, 17beta-estradiol: E2) on testicular gene expressions. Male C57BL/6J mice, 1 day after birth, were subcutaneously injected with DES or E2 (3 micrograms/mouse/day) for 5 days, and then they were raised for 8 weeks. In morphological observation of 8-week-old mice testes, spermatozoa were absent from many seminiferous tubules in DES-treated mice testes, but there was no change in E2-treated mice testes. Analysis of in-house cDNA microarray (mouse cDNA 889 genes) revealed that 17 genes were altered in DES-treated mice testes at 8 weeks of age, compared to each control. Real-time reverse transcription-polymerase chain reaction (real-time RT-PCR) analysis of these genes revealed that some genes, which were changed in E2-treated testis, were the same as in DES-treated testis, whereas in other cases there was a difference between DES-treated and E2-treated testis. The present results suggest that each exogenous estrogenic compound has both a common gene expression change pattern and its own testicular gene expression change pattern. Mol. Reprod. Dev. 67: 19-25, 2004.

Animals↗

PubMed2006

Proteomics as a route to identification of toxicity targets in environmental toxicology.

Ecotoxicology describes a three-way relationship between ecosystems, chemical pollutants and living organisms. It is predicated on the fact that chemical pollution can exert toxic effects on organisms at the individual and population levels. These toxic effects may provide important information to supplement chemical analysis of environmental samples and aid in assessing the environmental quality of specific ecosystems. Traditionally, effects have been detected by means of biomarkers which, of necessity, were often molecules or processes known to be affected by pollutants. Proteomics provides a means of achieving high-throughput analysis of effects on protein populations and sub-populations with the potential to identify novel biomarkers. This review summarises the main approaches currently used in this area and assesses the potential of proteomics for identification of novel toxicity targets.

Chromatography↗

PubMed2025

BMDx2: A Tool for Integrating Toxicogenomics-Based Dose-Dependency Analysis and AOP-Based Mechanistic Insights.

Despite the advent of mechanistic toxicology using omics data to link molecular perturbations with systemic outcomes, regulatory toxicology still lacks the application of mechanism-anchored metrics from such data. This is partially because traditional gene-centric analysis often falls short of linking molecular changes to adverse outcomes. To address this gap, BMDx2, an open-source tool that transforms multi-dose toxicogenomics datasets into quantitative, mechanistic evidence for human chemical safety assessment is developed. BMDx2 couples benchmark-dose modeling with Adverse Outcome Pathway (AOP) enrichment to derive transcriptomic-based points of departure, enabling potency ranking, chemical prioritization, and mechanistically anchored explanations of the effect of chemical exposures. BMDx2 can process a broad range of data, including DNA microarray and RNA sequencing studies. Here, case studies are used to illustrate the versatility of BMDx2 in characterizing the mechanism of action of chemicals. An initial case study on carbon nanotubes exposure applies integrative analysis of transcriptomics and genome-wide DNA methylation data, uncovering cellular reprogramming processes underlying fibrosis. A second case study on bleomycin exposure demonstrate how transcriptomic data alone can be mapped to fibrosis-related AOPs in a standardized, regulatory appropriate manner. Together, these examples show how BMDx2 supports the regulatory application of toxicogenomics and accelerates mechanism-based chemical safety evaluation.

Toxicogenetics↗

PubMed2007

Toxicogenomics applied to predictive and exploratory toxicology for the safety assessment of new chemical entities: a long road with deep potholes.

Toxicology is the perturbation of metabolism by external factors such as xenobiotics, environmental factors or drugs. As such, toxicology covers a broad range of fields from studies of the whole organism responses to minute biochemical events. Mechanistic toxicogenomics is an attempt to harness genomic tools to understand the physiological basis for a toxic event based on an analysis of transcriptional, translational or metabolomic profiles. These studies are complicated by non-toxic adaptive responses in transcript, protein or metabolite expression levels that have to be distinguished from those that are proximally related to the toxic event. Substantial progress has been made on the identification of biomarkers and the establishment of screens derived from such toxicogenomics studies. The ultimate goal, of course, is predictive toxicogenomics, which is an attempt to infer the likelihood of occurrence of a toxic event with exposure to a new agent based upon comparative responses with large databases of gene, protein or metabolite expression data. Gene expression databases are currently limited by the fact that measurable toxic phenotypes generally precede or at best coincide with the earliest observable changes in transcriptional profiles. Unfortunately, predictive protein databases have been limited by technical difficulties. Metabonomics-based databases, which would probably have the highest predictive value, are limited in turn by the inability to perform high dose studies in humans. This chapter will conclude by reviewing those elements of toxicogenomics that apply specifically to the development of anti-infectives and the potential for accurately modelling the toxicity of future drugs.

Animals↗