Page 50 - Academic Press Encyclopedia of Physical Science and Technology 3rd InOrganic Chemistry

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Encyclopedia of Physical Science and Technology EN002F-55 May 22, 2001 21:6

138 Bioinorganic Chemistry

agents have been approved for use as tumor imaging In considering ion presence in the body, inorganic
agents. Other compounds are being developed for uses chemists are concerned with the amount of a metal com-
as diverse as bowel markers, susceptibility agents for dy- plex that is consumed, the types of complexes that are con-
namic/functional MRI, blood flow agents, and lympho- sumed, and the enzymes and processes involved with their
graphic agents. The unique ability of inorganic ions to transport into the blood stream. In cases of nutritional de-
contain multiple unpaired spins means that MRI contrast ficiency of zinc documented in Iran in the 1940s, patients
agents are exclusively inorganic compounds. displaying growth retardation, hypogonadism, severe ane-
mia, hepatosplenomegaly, rough and dry skin, and mental
lethargy were found to have diets of unleavened bread
G. Chelation Therapy
with negligible intake of animal protein. Geophagia, the
When the concentration of an inorganic ion is above practice of clay eating, was also prevalent in the areas of
the level where the body cannot return it to homeosta- incidence. As a result of this poor diet, zinc was effec-
sis through genetically controlled regulatory pathways, tively lacking. The anemias were completely corrected by
the ion is toxic. Therapy must be provided to a patient to the administration of oral zinc or a combination of animal
decrease the toxicity of and ultimately remove the inor- protein, which contains zinc, and iron sulfate.
ganic ion from the body. The most widely used method to Menkes disease is a fatal genetic disorder with a
remove ions from the body is chelation therapy. widespread defect in copper transport. Most patients,
Chelation therapy is characterized by addition of a when untreated, die by 3 years of age. The basic biochem-
molecule,achelatingagent,thatbindstothemetalofinter- ical defect in Menkes patients is an inability to absorb
estandremovesitfromthebody.Mostchelatingagentsare copper through the intestine; the inability to distribute cop-
organic molecules containing multiple thiols, carboxylic per to and within cells is also included in the mechanism
acids, alcohols, hydroxamate, or amine groups capable of Menkes pathology. Treatment with copper histidine,
of binding the metal. The effectiveness of a particular Cu(His) 2 , is the only available treatment for Menkes dis-
chelating agent is dependent on several factors including ease. Interestingly, no other copper salts have been found
competing metals and ligands, dynamics of circulation, to work. The mechanism of efficacy of Cu(His) 2 is un-
compartmentalization, and metabolism of the chelating clear. One hypothesis is the interplay between histidine
agent. The ideal chelating agent would be one that has and albumin in the transport of copper across membranes.
an extremely high binding constant and specificity toward Another disease related to a dysfunction in copper
the target ion. It would be nontoxic and orally adminis- metabolism is Wilson’s disease. Unlike in Menkes’ pa-
tered. It would be able to diffuse as freely through the tients, copper in Wilson’s patients is readily absorbed
body as the target ion and be excreted from the body with through the intestine and into the cell. Within the cell,
high efficiency once it has bound the target ion. In reality, however, abnormally low levels of the copper-storage pro-
no chelating agents meet all these criteria and few come tein ceruloplasmin are present. As a result, copper accu-
close. mulates in the cytosol and is eventually released into the
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The siderophore desferriferrioxamine b, Desferal ,is blood stream. The clinical manifestations of Wilson’s dis-
used to treat conditions of iron overload in patients suffer- ease are liver disease and neurological damage.
ing from the genetic blood disorder β-thalassemia major.
The drug has a high affinity and specificity for Fe(III) and
I. Other Drugs
efficiently removes this ion from the body. The drug must
be administered as a subcutaneous infusion as it is not Several other inorganic compounds that either do not fall
orally active. Patients who do not comply with the rigor- into the above categories or whose mechanisms of action
ous regimen of administration succumb to the fatal effect are largely unknown are also employed as pharmaceuti-
of iron overload. cals. These include lithium drugs such as Li 2 CO 3 for the
treatment of manic–depressive disorder. The mechanism
of lithium is not fully understood, although it must have
H. Inorganic Ion Deficiency
an effect on the transmission of neuronal signals. Also in-
Because certain metal ions are essential for the function cluded are gold drugs, such as aurofin, for the treatment
of many enzymes, it is imperative not only that they be of arthritis, for which the mode of action also is largely
present in the body, but also that they be transported prop- unknown. One theory suggests that the thiophilic nature
erly into the necessary cells and to the necessary protein. of gold prevents the formation of disulfide bonds, which
A dysfunction in any of these mechanisms will be detri- can lead to protein insolubility. Another example is bis-
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mental to an organism. Below are brief descriptions of muth subsalicylate, Pepto-Bismol , for the treatment of
metal uptake. upset stomach and prevention of ulcers. Its mechanism of