Essentiality Toxicity Carcinogenicity Lead(Pb) Exposure Toxicokinetics Toxicity Neurologic, Neurobehavioral, and Developmental Effects in Children Mechanisms of Effects on the Developing Nervous System Peripheral Neuropathy Hematologic Effects Renal Toxicity Lead and Gout Effects on Cardiovascular System Immunotoxicity Bone Effects Reproductive Effects Birth Outcomes Carcinogenicity Other Effects Dose Response Treatment Organic Lead Compounds Mercury (Hg) Exposure Disposition and Toxicokinetics Metabolic Transformation Cellular Metabolism Toxicology Biological Indicators Treatment Nickel (Ni) Exposure Toxicokinetics Essentiality Toxicity Nickel Carbonyl Poisoning Dermatitis Indicators of Nickel Toxicity

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Toxic effects of metals

Zinc is known to be indispensable to growth and development and transmission of the genetic message. It does this through a remarkable mosaic of zinc binding motifs that orchestrate all aspects of metabolism. There are now nearly 200 three dimensional structures for zinc proteins, representing all six classes of enzymes and covering a wide range of phyla and species. These structures provide standards of reference for the identity and nature of zinc ligands in other proteins for which only the primary structure is known. Three primary types of zinc sites are apparent from examination of these structures: structural, catalytic and cocatalytic. The most common amino acids that supply ligands to these sites are His, Glu, Asp and Cys. In catalytic sites zinc generally forms complexes with water and any three nitrogen, oxygen and sulfur donors with His being the predominant amino acid chosen. Water is always a ligand to such sites. Structural zinc sites have four protein ligands and no bound water molecule. Cys is the preferred ligand in such sites. Cocatalytic sites contain two or three metals in close proximity with two of the metals bridged by a side chain moiety of a single amino acid residue, such as Asp, Glu or His and sometimes a water molecule. Asp and His are the preferred amino acids for these sites. No Cys ligands are found in such sites. The scaffolding of the zinc sites is also important to the function and reactivity of the bound metal. The influence of zinc on quaternary protein structure has led to the identification of a fourth type of zinc binding site, protein interface. In this case zinc sites are formed from ligands supplied from amino acid residues residing in the binding surface of two proteins. The resulting zinc site usually has the coordination properties of a catalytic or structural zinc binding site.

Zinc coordination sphere in biochemical zinc sites

The roles of iron in health and disease

https://www.oarsijournal.com/article/S1063-4584(03)00150-X/pdf

The role of reactive oxygen species in homeostasis and degradation of cartilage.

Objective

To assess the prevalence of clinical and biologic extrahepatic manifestations of hepatitis C virus (HCV) infection and to identify associations between clinical and biologic manifestations.



Methods

To analyze the natural history of extrahepatic manifestations of HCV infection, we reviewed only the data recorded prospectively during the first visit of 1,614 patients with chronic HCV infection, coming from a single monocenter cohort. Exclusion criteria were positivity for hepatitis B surface antigen or human immunodeficiency virus. The prevalence of dermatologic, rheumatologic, neurologic, and nephrologic manifestations; diabetes; arterial hypertension; autoantibodies; and cryoglobulins were assessed. Then, using multivariate analysis, we identified demographic, biochemical, immunologic, virologic, and liver histologic factors associated with the presence of extrahepatic manifestations.



Results

At least 1 clinical extrahepatic manifestation was observed in each of 1,202 patients (74%). Five manifestations had a prevalence >10%: arthralgia (23%), paresthesia (17%), myalgia (15%), pruritus (15%), and sicca syndrome (11%). Four biologic abnormalities had a prevalence >5%: cryoglobulins (40%), antinuclear antibodies (10%), low thyroxine level (10%), and anti–smooth muscle antibodies (7%). Only vasculitis, arterial hypertension, purpura, lichen planus, arthralgia, and low thyroxine level were associated with cryoglobulin positivity. By univariate and multivariate analyses, the most frequent risk factors for the presence of clinical and biologic extrahepatic manifestations were age, female sex, and extensive liver fibrosis.



Conclusion

Extrahepatic clinical manifestations are frequently observed in HCV patients and involve primarily the joints, muscles, and skin. The most frequent immunologic abnormalities include mixed cryoglobulins, antinuclear antibodies, and anti–smooth muscle antibodies. The most frequent risk factors for the presence of clinical and biologic extrahepatic manifestations are advanced age, female sex, and extensive liver fibrosis.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/1529-0131%28199910%2942%3A10%3C2204%3A%3AAID-ANR24%3E3.0.CO%3B2-D

Extrahepatic manifestations of chronic hepatitis C

In two young patients with acute hepatic porphyria syndrome and persisting paralyses, which increased in intensity during intermittent occurring crisis, the activity of erythrocyte porphobilinogen synthase (δ-aminolevulinic acid dehydratase) was found to be considerably diminished, below 1% of the value of normal control persons In contrast, the activity of uroporphyrinogen synthase was normal Both patients have been excreting high quantities of δ-aminolevulinic acid and porphyrins in urine for years Lead intoxication has definitively been excluded Since the relatives also show lower activities in porphobilinogen synthase, the disease of these two patients is probably a new enzymatic type of inherited acute hepatic porphyria, the excretion profile of which is qualitatively completely different from those of the known acute porphyrias The discovery of this porphyria confirms the theory of overlapping transition in the biochemical and clinical symptoms and analogies among acute hepatic porphyrias

New type of hepatic porphyria with porphobilinogen synthase defect and intermittent acute clinical manifestation.

Hepatobiliary implications and complications in protoporphyria, a 20-year study.

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.1840210604

Low prevalence of hepatitis C virus infection in porphyria cutanea tarda in germany

“Ethanol should be included in the list of drugs metabolized by hepatic microsomes” (Rubin and Lieber 1972) Such drugs stimulate their own metabolism, in which heme synthesis is involved, and affect porphyrin synthesis in various ways Alteration of porphyrin synthesis in an organism without hereditary and acquired toxic disturbances of porphyrin metabolism is an adaptive response Generally, these adaptive responses elicited by alcohol or other drugs in an organism without preexistent derangements in the heme biosynthesis sequences do not lead to clinical consequences However, certain drugs, including alcohol, are capable of expressing not only the latent but also the clinical phase of different porphyrias Especially acute hepatic porphyrias are triggered by drugs and/or alcohol and have therefore been designated as “pharmacogenetic diseases” (Kalow 1962) In addition, alcohol is the most frequent manifesting and aggravating factor in chronic hepatic porphyria, including porphyria cutanea tarda, which is genetically predetermined in some of the patients (Doss 1982; Kushner 1982) The clinical-biochemical interactions between alcohol and porphyrin/heme biosynthesis involve three main aspects: 

1

Triggering the biochemical and clinical manifestation of acute and chronic hepatic porphyrias




2

Development of symptomatic disturbances in porphyrin metabolism as secondary coproporphyrinuria and secondary protoporphyrinemia




3

Inhibition and stimulation of certain enzymes in the heme biosynthetic chain

/pdf/alcohol-and-porphyrin-metabolism-3z8a2vba07.pdf

Manfred O. Doss

Papers

New type of hepatic porphyria with porphobilinogen synthase defect and intermittent acute clinical manifestation.

Hepatobiliary implications and complications in protoporphyria, a 20-year study.

Low prevalence of hepatitis C virus infection in porphyria cutanea tarda in germany

Alcohol and porphyrin metabolism.

Singlet oxygen inactivates fibrinogen, factor V, factor VIII, factor X, and platelet aggregation of human blood.