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Hi,
I am looking for some literatures of studying pharmacokinetic and/or
pharmacodynamics interactions of metals such as lead, mercury, and
arsenic
in animals or humans, and the PK/PD interactions between metals and VOCs
as well. Can someone provide information on these issues? Thanks a lot.
Sheng-Wei
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Sheng,
The kinetics of a metal in the body is related to its valence and
ionization
potential. How these factors change (or do not change) as the metal
travels
through the body will influence both PK and PD. These two factors
determine
how the metal may gain access systemically, what the metal will bind to,
where the metal complex will go in the body, and how it will be
metabolized
and eliminated from the body. The PD effects of the metal are mainly
dependent on what the metal has found to form a complex with, but
generally,
the more
lipophilic the metal can be made (through complexation with organic
substrates) the more toxic it will be. The best information on
ADME-PK/PD issues is likely to found in the toxicology literature.
I am sure a search of medline will produce many good articles, but here
are
a few references to get you started:
Buchet JP, Pauwels J, Lauwerys R. (1994) Assessment of exposure to
inorganic
arsenic following ingestion of marine organisms by volunteers.
Environmental
Research; 66(1):44-51.
Venugopal, B. and Luckey, T.D. (1978) Metal Toxicity in Mammals. New
York,
Plenum Press.
NAS. (1977) Medical and Biological Effects of Environmental Pollutants:
Arsenic. National Academy of Sciences, Washington, D.C.
Rosner, M.H. and Carter, D.E. (1987) Metabolism and excretion of gallium
arsenide and arsenic oxides by hamsters following intratracheal
instillation. Fundamental and Applied Toxicology; 9: 730-737.
Jonathan Monteleone (MS), j.monteleone.at.auckland.ac.nz
Dept of Pharmacology & Clinical Pharmacology, School of Medicine
85 Park Rd, Private Bag 92019, Auckland, New Zealand
Work phone: +64 (9) 3737599 ext 86732
Pharmacometric Resources at
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/pkpd/
pkpd.htm
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Dear Professor Monteleone,
I read with interest your comments on metal toxicity. Do you have any
references on the toxicity of borinic acid derivatives (the boron has
two carbon substituents) vs. boronic acid derivatives (the boron has one
carbon and two oxygen substituents).
Thank you,
Ving J. Lee
Anacor Pharmaceuticals, Inc.
Palo Alto, California 94303
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Ving,
I conducted a search on PubMed, using the Boolean feature (link below):
http://www.ncbi.nlm.nih.gov/PubMed/boolean.html
Try putting in "boron and toxicity and review" and you can get started.
Other key words will also help. Best wishes. Harold
Harold Boxenbaum, Ph.D.
Pharmaceutical n Medical n Biotechnology - Nutraceutical Consultant
Arishel Inc.
14621 Settlers Landing Way
North Potomac, MD 20878-4305
Phone: 301-424-2806
Fax: 301-424-8563
E-Mail: harold.at.arishel.com
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Ving,
I have not worked with Boron derivatives before, and as Harold
suggested,
PubMed is a great place to start. In fact, a few google searches
(www.google.com) using words like boron physicochemical "borinic acid"
"boronic acid" toxicity etc. yielded quite a few interesting links that
may
be worthwhile for you to take a look at:
http://www.who.int/docstore/water_sanitation_health/GDWQ/Chemicals/
boronsum.htm
http://chemlab.pc.maricopa.edu/periodic/b.html
http://www.pubmedcentral.gov/articlerender.fcgi?
tool=pmcentrez&artid=283830
http://www.knowledgebank.irri.org/riceDoctor_MX/Fact_Sheets/
DeficienciesToxicities/Boron_toxicity.htm
And some references I also found Boron information in:
Klaassen, C. D. (1986). Casarett and Doull's Toxicology, the Basic
Science
of Poisons. New York, Macmillan Publishing Company.
Calabrese, E.J. (1991). Multiple Chemical Interactions. Michigan, Lewis
Publishers, INC.
The book, Venugopal, B. and Luckey, T.D. (1978) Metal Toxicity in
Mammals.
New York, Plenum Press. also has some useful chapters on the basics of
metal interactions in biological environments, which may be useful.
I did find some chemical structure figures for borinic acid
derivatives, and
from structure you can sometimes predict toxicity. I have heard of a
software program (cant recall the name, but it was something like
"meta-bol
predict") that allows you to input the parent molecule structure and the
program will predict the metabolites based on phase I & II metabolism,
and
then offer possible resulting toxicity. I am not sure if the software
works
for metal complexes. Anybody else know of software to take a molecule
from
parent through metabolite to possible toxic outcomes?
Just looking at the structure of the borinic acid derivatives suggests
they
are less easily metabolized compared to boronic acid derivatives, and
the
potential for free radical production appears greater with the borinic
acids, when they are metabolized, compared to the boronic acids. It is
all
about the interaction between how electrons move around metal complexes
and
the influence of the surrounding matrix to faciliate the electron
movement.
The borinic acids with the aromatic functional groups give an enormous
ability to shift the electons around the complex compared to the boronic
acid complexes. The metal complex is like the delivery system, and the
metal itself and the remaining complex (after the metal is removed) are
ultimately the cause for toxicity once the metal has been freed from the
complex. So, the ionic state of the "freed" metal and the remaining
complex
produce the damage.
In lieu of actual literature on borinic acid derivative toxicity, some
basic
bioinorganic chemistry provides insight about the toxicity a metal
complex
may produce, and suggests possible experiments for actually determining
the
toxicity.
Cheers -Jon
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)