Drug-induced liver injury (DILI) with high incidence and prevalence rates is a potentially severe adverse drug reaction (ADR) especially in susceptible patients, and is concomitantly challenging for drug development, clinical practice, and regulation. Nonetheless, there are no sensitive or specific parameters to detecting DILI. The ADRs, particularly those that result in life-threating DILI, are a major cause of drug failure in clinical trials and drug withdrawals. The currently annotated serum and new emerging biomarkers can be used to identify hepatotoxicity in general and provide, to a certain extent, a tool for mechanistic distinction. New biomarkers to diagnose and predict DILI evolution are under study and hopefully gain the benefits from these novel tools in the near future. The facility of more advanced scientific and regulatory guidance for liver safety assessment will depend on validating the new diagnostic markers in the ongoing DILI registries, biobanks and public-private partnerships. The limited predictive model of in silico models can be mostly attributed to the complex nature of DILI, various molecular mechanisms underlying DILI, poor in vitro-in vivo correlation, a scarcity of human DILI data in addition to numerous additional factors contributing to DILI, namely dosage, administration duration, drug interactions, pharmacokinetics profile, age, gender, pre-existing disease, disease state, polymorphism, environmental factors and exposure to other foreign compounds, environmental factors, exposure to other foreign compounds. As such, it is not surprising that DILI prediction is extremely difficult if not entirely impossible. Despite those difficulties, there have been efforts to develop in silico models to predict hepatotoxicity in the last decade. This chapter is not intended to comprehensively cover every published in silico DILI models. Instead, a number of DILI predictive models in every aspect are briefly described.
The over-produced reactive oxygen species (ROS) and reactive nitrogen species (RNS) in inflammatory diseases, such as neurodegenerative diseases, Type 2 diabetes (T2D), cardiovascular injury and autoimmune disease, would accompany a significant increase in protein tyrosine nitration that attributes to initiation and progression of these diseases. Understanding the most biologically relevant nitration pathways in vivo, identifying nitration sites of the specific nitrated proteins, and unveiling the nitration-induced biological consequences would provide invaluable information for the clinical understandingly of onset and progression of the associated diseases and also for the design of clinical interventions by catalytically decomposing and scavenging RNS/ROS for prevention of protein nitration in vivo.
Neurodegenerative pathologies represent a serious health-related public issue. Currently, the scientific community points to many biological targets but the cause of these disorders remains unclear. In this complex scenario, melatonin has emerged as a "magic bullet" to counteract most of the physiopathological events that trigger neurodegenerative disorders. Since its production drops during the aging process, this indoleamine may have a particular significance in the age-related diseases. Furthermore, the multiplicity of actions of melatonin in the central nervous system, reducing aberrant accumulation and aggregation of disease-specific proteins, modulating the immune response and neuroinflammation as well as enhancing the neurogenesis, among others, make of this indoleamine a promising molecule against neurodegeneration. In this chapter we summarized the neuroprotective potential of melatonin counteracting the main physiopathological features involved in neurodegenerative disorders.
This chapter provides a road map for applying in silico models, read-across, and cluster analysis as regulatory tools. Building the foundation of utilizing QSAR models in risk assessment starts with grouping (clustering) structurally related chemicals into categories. The next step is to summarize the toxicology data of the clustered chemicals in tabular form to identify the data gaps and trends relating incremental structural changes to biological activity. By reading-across (bridging) from a data-rich surrogate compound(s) to the other clustered chemical(s) lacking data, the toxicology data from the surrogate molecule(s) can be “bridged” to fill the data gaps of the untested compound(s). The chapter also summarizes a few examples of the application of molecular structure-based toxicology and toxicokinetics predictions from read-across to bridge data gaps for substances lacking the animal data commonly understood to be necessary for safety assessment.
Marijuana remains one of the most commonly used psychoactive substances across the globe, yet conclusive evidence about the toxic effects resulting from its exposure is still insufficient. The dearth of high-quality information specific to the toxic effects and thus, potential health implications of marijuana use and related exposures, constitute a critical research need given the emerging liberalization and increasing rates of marijuana use (Glantz et al., 2018 [1]; Hall and Degenhardt, 2009). Marijuana is most commonly smoked, is widely viewed as being less harmful compared to tobacco (Padilla et al., 2014 [3]), and now ranks as the world's second most-popular combustible product following tobacco cigarettes (UNODC, 2018; Murray et al., 2007 [5]; Wei et al., 2016, 2018). Within this context, it is anticipated that the general population's exposure to secondhand marijuana smoke (SHMS) is likely to increase (Wang et al., 2016 [8]). In this chapter, we present an overview of the existing evidence regarding occurrences, biological analyses, and potential adverse health effects of SHMS exposure. We focus our discussion on the recent progress in biomonitoring approaches utilized for assessing SHMS exposure, including selection of biological matrices and exposure biomarkers, and development of the bio-analytical assays. We highlight the challenges that require consideration when interpreting SHMS biomonitoring data in exposure assessments, and provide some suggested directions for future research.
Carbon nanotubes (CNTs) are newly developed engineered nanomaterials with remarkable properties employed for a wide range of numerous commercial and industrial applications. However, CNT exposure in various settings is a significant concern as CNTs are readily inhaled into human lungs resulting in debilitating pulmonary responses, most notably fibrosis. Several rodent studies have demonstrated consistent adverse pulmonary effects including inflammation and granulomatous lesions leading to interstitial and subpleural fibrosis. Some of the crucial mechanistic steps involved during CNT-induced fibrosis range from generation of reactive oxygen species, inflammation, release of proinflammatory cytokines that initiate several intracellular cell signaling cascades, and expansion of the pool of myofibroblast via epithelial–mesenchymal transition. Furthermore, physicochemical properties of CNT including length and surface functionalization can influence their fibrogenic activity. The objective of this chapter is to review, summarize, and discuss major cellular and molecular mechanisms driving CNT-induced fibrogenesis.
Colorectal cancer is one of the leading causes of morbidity and mortality globally, which accounts for 0.7 million deaths in 2015. Despite the fact that tremendous advancement had been achieved in research and development in medicine, the colorectal cancer-related deaths are ascending continuously thus, the research community has come up with chemoprevention, a novel and innovative way to reduce colorectal cancer. Chemoprevention therapies use several pharmacological agents having negative influences on human health and to overcome this natural products are used now-a-days, as being reported. Various epidemiological studies have associated the consumption of some dietary phytochemicals with lower risk of colorectal cancer development. Here in this chapter, we summarize the chemopreventive effect of dietary phytochemicals, their availability, in vitro and in vivo effects on colorectal cancer, and clinical studies. This review describes the promising effect of dietary phytochemicals in colorectal cancer intervention.
In developmental toxicity, the evaluation of early biomarkers may be predictive of later developmental outcomes. Over the last few years, new models have been proposed for predicting developmental effects through the analysis of different effect biomarkers which have been supported by the need to implement the 3Rs (replacement, refinement, and reduction) during laboratory experimentation. In this regard, the use of the early life stages of the zebrafish (Danio rerio) has become an accepted model for toxicological studies and an important tool in translational research. This chapter describes the most common and validated biomarkers used in biochemical and genetic approaches using this animal model and presents examples of many different types of biomarkers for many classes of toxicological compounds. Although this chapter outlines the potential of the proposed biomarkers and the early life stages of zebrafish for utilization as a part of biomonitoring systems, a number of experiments are required to examine and establish the utility of the selected biomarkers to predict the whole-organism and population-level responses.
Trichloroethylene (TCE) is a widely used industrial solvent and a common environmental contaminant. It has been reported that TCE exposure is associated with a wide range of diseases, including cancer, immune system diseases, and congenital heart defect. TCE is metabolized in vivo through two main pathways, Cytochrome P450-dependent oxidation and glutathione conjugation. The adverse effects of TCE in different target tissues may be partly due to specific reactive metabolites. In this review, we will evaluate the evidence on carcinogenicity, immunotoxicity, and cardiac developmental toxicity of TCE and will discuss the potential underlying molecule mechanisms.
This chapter introduces the bioactivation and toxicity of furanoterpenoids, particularly their hepatotoxicity. It starts with a brief description of biosynthesis of furanoterpenoids, followed by mechanisms of metabolic activation of furan-containing compounds and the interactions of reactive metabolites of furanoids with proteins. A total of five furanoterpenoids, i.e., 4-ipomeanol, teucrin A, diosbulbin B, 8-epidiosbulbin E acetate, and toosendanin, are discussed as examples. The chapter covers (1) the natural source and toxicities of the furanoterpenoids; (2) identification of reactive metabolites and major cytochromes P450 involved in the metabolic activation of the furan-containing compounds; and (3) protein modifications induced by the reactive metabolites of the furanoids. It also describes a newly developed approach to screen potentially harmful furan-containing compounds from complicated mixtures.
Among the vast array of secondary metabolites produced by plants, anthraquinones (AQs) are the group of compounds produced by different plants of various families such as Polygonaceae, Rhamnaceae, Rubiaceae, Fabaceae, Xanthorrhoeaceae, Leguminosae, and Liliacae. Owing to their biological and chemical diversity, AQs have wide industrial applications in food, pharmaceutical, and paper industries. Despite their diverse application, anthraquinones have been reported to be toxic to experimental animals. However, very little is known about their toxicity on the human population. In this chapter, the metabolic routes for the biosynthesis of AQs in plants have been described. Efforts have been focused on the profile of AQs present in different plant species and their toxic effects on the various animal models and in humans.
This chapter first describes the potential of stem cells in diverse biopharmaceutical applications, such as replacement therapy, disease modeling, and drug development. On the other hand, stem cells can become the targets of various potential toxicities in the body. In this context, an overview of stem cells as objects in toxicology as well as various experimental approaches to analyze the effects of toxic substances including anticancer drugs is presented, single-cell methods and natural microenvironment-mimicking models among them. Further, anticancer drugs (both conventional and targeted) and their molecular targets are described, with advances and challenges in their use as well as current directions in their combination and development. Then, recent knowledge about adult stem cell response to anticancer therapy is presented, paying attention to the molecular mechanisms of cell death induction and resistance, and uncovering the possible role of stem cell differentiation state during the anticancer treatment. Finally, various ideas, suggestions, and experimental data to protect adult stem cells during cancer therapy are presented.
The somatic mutation theory of tumorigenesis predicts that increased tumor risks posed by chronic, low-level exposures to mutagenic chemical carcinogens have linear-no-threshold low-dose dose-response (LDDR) relationships. A recently proposed alternative, dysregulated adaptive hyperplasia (DAH) theory does not imply this expectation, positing instead that tissue-specific tumors arise most efficiently only from a(ny) stem cell that (i) happens to be "activated" epigenetically (via a specific microRNA expression profile) to initiate and maintain a state of adaptive hyperplasia (AH) and (ii) additionally incurs a single, dysregulating mutation preventing transduction of the signal that normally terminates AH in that tissue (Bogen, 2013). Accumulating data support the hypothesis that sustained oxidative stress associated with elevated reactive oxygen species (ROS) triggers Keap1-Nrf2-ARE-mediated AH-stem-cell recruitment. Because Nrf2 activation is here demonstrated to have an unambiguously J-shaped LDDR, Nrf2 activation (even by chemical mutagens) could drive DAH-induced tumorigenesis. If so, despite experimental or epidemiologic evidence of increased tumor risk at higher doses, an Nrf2-driven DAH mechanism implies that sufficiently low-level chronic exposures to (even mutagenic) chemical carcinogens may typically increase tumor risk with a highly sublinear or threshold-like LDDR. This "Nrf2-DAH" theory is discussed in relation to key underlying concepts (stem cells, ROS, the Keap1-Nrf2-ARE pathway, inflammation, and autophagy), as well as experimental data that bear on this theory's plausibility and on its LDDR implications.
DNA interstrand cross-links (ICLs) are the sources of the cytotoxicity of many anticancer agents. DNA cross-linking agents are used as anticancer agents, for DNA damage and repair study, for nucleic acid detection, and for construction of DNA nanomaterials. This chapter summarizes various novel methods and chemical reagents recently developed for inducing DNA ICL formation, the mechanisms involved for DNA cross-linking, and their applications. It starts by presenting photoinduced DNA ICL formation via [2+2] cycloaddition reaction, quinone methide, or carbocation formation. It then discusses novel DNA cross-linking agents activated by various chemical agents, including the arylboronate or boronic acid derivatives activated by hydrogen peroxide, silyl-protected bifunctional phenol derivatives triggered by fluoride, and phenyl selenides or furan analogs activated by oxidation reagents. General mechanisms involved formation of alkylating species, including quinone methide, nitrogen mustard, methide analogs, and enal formation. Enzyme-activated DNA cross-linking agents and their application for targeting cancer cells are also explained. By the end of the chapter, DNA ICL formation induced by "click" chemistry is highlighted.
This chapter introduces the bioactivation and toxicity of bis-benzylisoquinoline alkaloid, particularly their pulmonary toxicity. It starts with a brief description of pharmacological activities of bis-benzylisoquinoline alkaloids, followed by mechanisms of metabolic activation of para-methylene phenol containing compounds and the interactions of reactive metabolites of isoquinoline alkaloids with proteins. A total of four bis-benzylisoquinoline alkaloids, i.e., dauricine, tetrandrine, neferine, and berbamine are discussed as examples. The chapter covers (1) the natural source and pharmacological activities of the bis-benzylisoquinoline alkaloids; (2) identification of reactive metabolites and major cytochromes P450 involved in the metabolic activation of the para-methylene phenol containing compounds; and (3) protein modifications induced by the reactive metabolites of the isoquinoline alkaloids. It also describes a newly developed approach to screen potentially harmful para-methylene phenol containing compounds from complicated mixtures.
Topoisomerases are critical cellular enzymes involved in the regulation of DNA topology. These enzymes generate transient single-(type I) and double-strand (type II) DNA breaks in order to relieve topological strain due to replication, transcription, and chromosome segregation. Disruption of topoisomerase activity has been used as a target of antineoplastic therapy for several decades. While some agents have been used for over 30 years, many new compounds continue to be explored. This chapter will focus on reviewing the function, mechanism, and targeting of mammalian type II topoisomerases. In particular, we will highlight newer compounds that are under examination and explore new strategies for targeting topoisomerase II in humans that may provide alternatives to existing therapies.
Among Parkinson's disease (PD) toxin models, MPTP/MPP+ has been the most popular, extensively characterized, and widely used to identify the cellular mechanisms associated with the selective degeneration of dopaminergic neurons in PD. A number of recent studies have found some gaps and weaknesses in the generally accepted mechanism especially with regard to the selective dopaminergic toxicity of the model. Accumulating evidence suggests that the inherent physiological predisposition of dopaminergic neurons to generate high oxidative stress, especially when exposed to various environmental and genetic factors and their inability to cope with these conditions effectively, could contribute to their selective destruction. However, the current models for the selective dopaminergic toxicity of MPTP/MPP+ have not taken into account the unique susceptibilities of these neurons. The focus of this chapter is to discuss the discovery, current status, gaps, and weaknesses of the mechanism of the specific dopaminergic toxicity of the MPTP/MPP+ model.
