Heavy metals are naturally occurring elements that have a high atomic weight and a density at least five times greater than that of water. Their multiple industrial, domestic, agricultural, medical, and technological applications have led to their wide distribution in the environment, raising concerns over their potential effects on human health and the environment. Their toxicity depends on several factors including the dose, route of exposure, and chemical species, as well as the age, gender, genetics, and nutritional status of exposed individuals. Because of their high degree of toxicity, arsenic, cadmium, chromium, lead, and mercury rank among the priority metals that are of public health significance. These metallic elements are considered systemic toxicants that are known to induce multiple organ damage, even at lower levels of exposure. They are also classified as human carcinogens (known or probable) according to the US Environmental Protection Agency and the International Agency for Research on Cancer. This review provides an analysis of their environmental occurrence, production and use, potential for human exposure, and molecular mechanisms of toxicity, genotoxicity, and carcinogenicity.

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Heavy metal toxicity and the environment.

Oxidative mechanisms in the toxicity of metal ions

Organismal life encounters reactive oxidants from internal metabolism and environmental toxicant exposure. Reactive oxygen and nitrogen species cause oxidative stress and are traditionally viewed as being harmful. On the other hand, controlled production of oxidants in normal cells serves useful purposes to regulate signaling pathways. Reactive oxidants are counterbalanced by complex antioxidant defense systems regulated by a web of pathways to ensure that the response to oxidants is adequate for the body's needs. A recurrent theme in oxidant signaling and antioxidant defense is reactive cysteine thiol–based redox signaling. The nuclear factor erythroid 2–related factor 2 (Nrf2) is an emerging regulator of cellular resistance to oxidants. Nrf2 controls the basal and induced expression of an array of antioxidant response element–dependent genes to regulate the physiological and pathophysiological outcomes of oxidant exposure. This review discusses the impact of Nrf2 on oxidative stress and toxicity and how...

/pdf/role-of-nrf2-in-oxidative-stress-and-toxicity-2utmvoa3ko.pdf

Role of nrf2 in oxidative stress and toxicity.

Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling.

https://www.njacs.org/wp-content/docs/2010-10-DrugMet-R-Evers.pdf

Membrane transporters in drug development.

▪ Abstract Among the heavy metal-binding ligands in plant cells the phytochelatins (PCs) and metallothioneins (MTs) are the best characterized. PCs and MTs are different classes of cysteine-rich, heavy metal-binding protein molecules. PCs are enzymatically synthesized peptides, whereas MTs are gene-encoded polypeptides. Recently, genes encoding the enzyme PC synthase have been identified in plants and other species while the completion of the Arabidopsis genome sequence has allowed the identification of the entire suite of MT genes in a higher plant. Recent advances in understanding the regulation of PC biosynthesis and MT gene expression and the possible roles of PCs and MTs in heavy metal detoxification and homeostasis are reviewed.

PHYTOCHELATINS AND METALLOTHIONEINS: Roles in Heavy Metal Detoxification and Homeostasis

The most trusted all-in-one overview of the biomedical and environmental aspects of toxicology - Now more complete, up-to-date, and in full color. It is a Doody's Core Title for 2015! New to the Eighth Edition Full-Color design to allow for a clearer interpretation of the basic components of toxicology featured throughout the text. Expanded tables, illustrations, and other visuals are updated with state-of-the-art standards that makes this edition even more current and relevant DVD with image bank features all tables and illustrations from the text in presentation-ready format. New Chapters include "Toxic Effects of Calories" and "Toxic Effects of Nanoparticles." The world's leading and most authoritative textbook on poisons has more to offer students, toxicologists, and pharmacologists than ever before. Now in full color, and thoroughly revised, the eighth edition of Casarett & Doull's Toxicology: The Basic Science of Poisons not only delivers a comprehensive review of the essential components of toxicology, it offers the most up-to-date, revealing, and in-depth look at the systemic responses of toxic substance available anywhere. Combined with the latest thinking by the field's foremost scholars plus solid coverage of general principles, modes of action, and chemical-specific toxicity, this landmark text continues to set the standard for toxicology references.

Casarett and Doull's toxicology : the basic science of poisons

The pregnane X receptor (PXR) is the molecular target for catatoxic steroids such as pregnenolone 16α-carbonitrile (PCN), which induce cytochrome P450 3A (CYP3A) expression and protect the body from harmful chemicals. In this study, we demonstrate that PXR is activated by the toxic bile acid lithocholic acid (LCA) and its 3-keto metabolite. Furthermore, we show that PXR regulates the expression of genes involved in the biosynthesis, transport, and metabolism of bile acids including cholesterol 7α-hydroxylase (Cyp7a1) and the Na+-independent organic anion transporter 2 (Oatp2). Finally, we demonstrate that activation of PXR protects against severe liver damage induced by LCA. Based on these data, we propose that PXR serves as a physiological sensor of LCA, and coordinately regulates gene expression to reduce the concentrations of this toxic bile acid. These findings suggest that PXR agonists may prove useful in the treatment of human cholestatic liver disease.

https://www.pnas.org/content/pnas/98/6/3369.full.pdf

The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity

▪ Abstract Metallothioneins (MT) are low-molecular-weight, cysteine-rich, metal-binding proteins. MT genes are readily induced by various physiologic and toxicologic stimuli. Because the cysteines in MT are absolutely conserved across species, it was suspected that the cysteines are necessary for function and MT is essential for life. In attempts to determine the function(s) of MT, studies have been performed using four different experimental paradigms: (a) animals injected with chemicals known to induce MT; (b) cells adapted to survive and grow in high concentrations of MT-inducing toxicants; (c) cells transfected with the MT gene; and (d) MT-transgenic and MT-null mice. Most often, results from studies using the first three approaches have indicated multiple functions of MT in cell biology: MT (a) is a “storehouse” for zinc, (b) is a free-radical scavenger, and (c) protects against cadmium (Cd) toxicity. However, studies using MT-transgenic and null mice have not strongly supported the first two propose...

Metallothionein: an intracellular protein to protect against cadmium toxicity.

Transporters influence the disposition of chemicals within the body by participating in absorption, distribution, and elimination. Transporters of the solute carrier family (SLC) comprise a variety of proteins, including organic cation transporters (OCT) 1 to 3, organic cation/carnitine transporters (OCTN) 1 to 3, organic anion transporters (OAT) 1 to 7, various organic anion transporting polypeptide isoforms, sodium taurocholate cotransporting polypeptide, apical sodium-dependent bile acid transporter, peptide transporters (PEPT) 1 and 2, concentrative nucleoside transporters (CNT) 1 to 3, equilibrative nucleoside transporter (ENT) 1 to 3, and multidrug and toxin extrusion transporters (MATE) 1 and 2, which mediate the uptake (except MATEs) of organic anions and cations as well as peptides and nucleosides. Efflux transporters of the ATP-binding cassette superfamily, such as ATP-binding cassette transporter A1 (ABCA1), multidrug resistance proteins (MDR) 1 and 2, bile salt export pump, multidrug resistance-associated proteins (MRP) 1 to 9, breast cancer resistance protein, and ATP-binding cassette subfamily G members 5 and 8, are responsible for the unidirectional export of endogenous and exogenous substances. Other efflux transporters [ATPase copper-transporting β polypeptide (ATP7B) and ATPase class I type 8B member 1 (ATP8B1) as well as organic solute transporters (OST) α and β] also play major roles in the transport of some endogenous chemicals across biological membranes. This review article provides a comprehensive overview of these transporters (both rodent and human) with regard to tissue distribution, subcellular localization, and substrate preferences. Because uptake and efflux transporters are expressed in multiple cell types, the roles of transporters in a variety of tissues, including the liver, kidneys, intestine, brain, heart, placenta, mammary glands, immune cells, and testes are discussed. Attention is also placed upon a variety of regulatory factors that influence transporter expression and function, including transcriptional activation and post-translational modifications as well as subcellular trafficking. Sex differences, ontogeny, and pharmacological and toxicological regulation of transporters are also addressed. Transporters are important transmembrane proteins that mediate the cellular entry and exit of a wide range of substrates throughout the body and thereby play important roles in human physiology, pharmacology, pathology, and toxicology.

Curtis D. Klaassen

Papers

Casarett and Doull's toxicology : the basic science of poisons

The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity

Metallothionein: an intracellular protein to protect against cadmium toxicity.

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

Metallothionein protection of cadmium toxicity.