Advances in Pharmacology

Cyclooxygenase (COX) isozymes, i.e., COX-1 and COX-2, are encoded by separate genes and are involved in the generation of the same products, prostaglandin (PG)G2 and PGH2 from arachidonic acid (AA) by the COX and peroxidase activities of the enzymes, respectively. PGH2 is then transformed into prostanoids in a tissue-dependent fashion due to the different expression of downstream synthases. Platelets present almost exclusively COX-1, which generates large amounts of thromboxane (TX)A2 , a proaggregatory and vasoconstrictor mediator...

Hypertension is a major healthcare issue that afflicts one in every three adults worldwide and contributes to cardiovascular diseases, morbidity and mortality. Bioactive lipids contribute importantly to blood pressure regulation via actions on the vasculature, kidney, and inflammation. Vascular actions of bioactive lipids include blood pressure lowering vasodilation and blood pressure elevating vasoconstriction. Increased renin release by bioactive lipids in the kidney is pro-hypertensive whereas anti-hypertensive bioactive lipid actions result in increased sodium excretion...

No abstract text is available yet for this article.

Breast cancer is a major health threat to women worldwide and the leading cause of cancer-related death. The use of organophosphorous pesticides has increased in agricultural environments and urban settings, and there is evidence that estrogen may increase breast cancer risk in women. The mammary gland is an excellent model for examining its susceptibility to different carcinogenic agents due to its high cell proliferation capabilities associated with the topography of the mammary parenchyma and specific stages of gland development...

Arsenic is an environmental toxicant that significantly enhances the risk of developing disease, including several cancers. While the epidemiological evidence supporting increased cancer risk due to chronic arsenic exposure is strong, therapies tailored to treat exposed populations are lacking. This can be accredited in large part to the chronic nature and pleiotropic pathological effects associated with prolonged arsenic exposure. Despite this fact, several putative mediators of arsenic promotion of cancer have been identified...

Arsenic is a naturally occurring metal carcinogen found in the Earth's crust. Millions of people worldwide are chronically exposed to arsenic through drinking water and food. Exposure to inorganic arsenic has been implicated in many diseases ranging from acute toxicities to malignant transformations. Despite the well-known deleterious health effects of arsenic exposure, the molecular mechanisms in arsenic-mediated carcinogenesis are not fully understood. Since arsenic is non-mutagenic, the mechanism by which arsenic causes carcinogenesis is via alterations in epigenetic-regulated gene expression...

Sarcomas are rare and heterogenous mesenchymal tumors occurring in soft tissue and bone. The World Health Organization Classification of sarcomas comprises more than hundred different entities which are very diverse in their molecular, genetic and epigenetic signatures as they are in their clinical presentations and behaviors. While sarcomas can be associated with an underlying hereditary cancer predisposition, most sarcomas developed sporadically without identifiable cause. Sarcoma oncogenesis involves complex interactions between genetic, epigenetic and environmental factors which are intimately related and intensively studied...

Canonical histone messenger RNAs (mRNAs) are transcribed during S phase and do not terminate with a poly(A) tail at the 3' end. Instead, the histone mRNAs display a stem-loop structure at their 3-end. Stem-loop-binding protein (SLBP) binds the stem-loop and regulates canonical histone mRNA metabolism. We previously demonstrated that exposure to arsenic, an environmental carcinogen, induces polyadenylation of canonical histone H3.1 mRNA, causing transformation of human cells in vitro. Arsenic decreased cellular levels of SLBP by inducing its proteasomal degradation and inhibiting SLBP transcription via epigenetic mechanisms...

Hexavalent chromium is a firmly established human carcinogen with documented exposures in many professional groups. Environmental exposure to Cr(VI) is also a significant public health concern. Cr(VI) exists in aqueous solutions as chromate anion that is unreactive with DNA and requires reductive activation inside the cells to produce genotoxic and mutagenic effects. Reduction of Cr(VI) in cells is nonenzymatic and in vivo principally driven by ascorbate with a secondary contribution from nonprotein thiols glutathione and cysteine...

Hexavalent chromium [Cr(VI)], a Group I carcinogen classified by the International Agency for Research on Cancer (IARC), represents one of the most common occupational and environmental pollutants. The findings from human epidemiological and laboratory animal studies show that long-term exposure to Cr(VI) causes lung cancer and other cancer. Although Cr(VI) is a well-recognized carcinogen, the mechanism of Cr(VI) carcinogenesis has not been well understood. Due to the fact that Cr(VI) undergoes a series of metabolic reductions once entering cells to generate reactive Cr metabolites and reactive oxygen species (ROS) causing genotoxicity, Cr(VI) is generally considered as a genotoxic carcinogen...

Arsenic-induced carcinogenesis is a worldwide health problem. Identifying the molecular mechanisms responsible for the induction of arsenic-induced cancers is important for developing treatment strategies. MicroRNA (miRNA) dysregulation is known to affect development and progression of human cancer. Several studies have identified an association between altered miRNA expression in cancers from individuals chronically exposed to arsenic and in cell models for arsenic-induced carcinogenesis. This chapter provides a comprehensive review for miRNA dysregulation in arsenic-induced cancer...

Arsenic is a potent carcinogen and poses a significant health concern worldwide. Exposure occurs through ingestion of drinking water and contaminated foods and through inhalation due to pollution. Epidemiological evidence shows arsenic induces cancers of the skin, lung, liver, and bladder among other tissues. While studies in animal and cell culture models support arsenic as a carcinogen, the mechanisms of arsenic carcinogenesis are not fully understood. Arsenic carcinogenesis is a complex process due its ability to be metabolized and because of the many cellular pathways it targets in the cell...

Tungsten is an emerging contaminant in the environment. Research has demonstrated that humans are exposed to high levels of tungsten in certain settings, primarily due to increased use of tungsten in industrial applications. However, our understanding of the potential human health risks of tungsten exposure is still limited. An important point we have learned about the toxicity profile of tungsten is that it is complex because tungsten can often augment the effects of other co-exposures or co-stressors, which could result in greater toxicity or more severe disease...

In a dynamic environment, organisms must constantly mount an adaptive response to new environmental conditions in order to survive. Novel patterns of gene expression, driven by attendant changes in chromatin architecture, aid in adaptation and survival. Critical mechanisms in the control of gene transcription govern new spatiotemporal chromatin-chromatin interactions that make regulatory DNA elements accessible to the transcription factors that control the response. Consequently, agents that disrupt chromatin structure are likely to have a direct impact on the transcriptional programs of cells and organisms and to drive alterations in fundamental physiological processes...

No abstract text is available yet for this article.

Cytochrome P450 enzymes (CYPs) that metabolize xenobiotics are expressed and active in the brain. These CYPs contribute to the metabolism of many centrally acting compounds, including clinically used drugs, drugs of abuse, and neurotoxins. Although CYP levels are lower in the brain than in the liver, they may influence central substrate and metabolite concentrations, which could alter resulting centrally-mediated responses to these compounds. Additionally, xenobiotic metabolizing CYPs are highly variable due to genetic polymorphisms and regulation by endogenous and xenobiotic molecules...

With the availability of detailed genomic data on all 57 human cytochrome P450 genes, it is clear that there is substantial variability in gene product activity with functionally significant polymorphisms reported across almost all isoforms. This article is concerned mainly with 13 P450 isoforms of particular relevance to xenobiotic metabolism. After brief review of the extent of polymorphism in each, the relevance of selected P450 isoforms to both adverse drug reaction and disease susceptibility is considered in detail...

The cytochromes P450s can be divided in two groups, those of high importance for endogenous functions being evolutionary quite stable and those participating in detoxification of drugs and other xenobiotics having less important endogenous functions. In the latter group extensive genetic diversity has been allowed and in addition this is of high importance for survival in different environments. The genetic polymorphisms in these genes have evolved to some extent based on dietary restrictions and environmental factors and have not been subject of conservation due to less importance for survival...

Cytochrome P450 enzymes play an important role in the pharmacokinetics, efficacy, and toxicity of drugs. Age-dependent changes in P450 enzyme expression have been studied based on several detection systems, as well as by deconvolution of in vivo pharmacokinetic data observed in pediatric populations. The age-dependent changes in P450 enzyme expression can be important determinants of drug disposition in childhood, in addition to the changes in body size and the other physiological parameters, and effects of pharmacogenetics and disease on organ functions...

Cynomolgus macaques (Macaca fascicularis, an Old World monkey) are widely used in drug development because of their genetic and physiological similarities to humans, and this trend has continued with the use of common marmosets (Callithrix jacchus, a New World monkey). Information on the major drug-metabolizing cytochrome P450 (CYP, P450) enzymes of these primate species indicates that multiple forms of their P450 enzymes have generally similar substrate selectivities to those of human P450 enzymes; however, some differences in isoform, activity, and substrate specificity account for limited species differences in drug oxidative metabolism...