DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

voluntarily replaced arsenic with other preservatives. Arsenic-treated
wood is thought to be safe unless burned (Hall, 2002). The major
source of occupational exposure to arsenic is in the production and
use of organic arsenicals as herbicides and insecticides. Exposure to
metallic arsenic, arsine, arsenic trioxide, and gallium arsenide also
occurs in high-tech industries, such as the manufacture of computer
chips and semiconductors.
Chemistry and Mode of Action. Arsenic exists in its elemental form
and trivalent (arsenites/arsenious acid) and pentavalent (arsenates/
arsenic acid) states. Arsine is a gaseous hydride of trivalent arsenic
that exhibits toxicities that are distinct from other forms. Organic
compounds containing either valence state of arsenic are formed in
animals. The toxicity of a given arsenical is related to the rate of its
clearance from the body and its ability to concentrate in tissues. In
general, toxicity increases in the sequence: organic arsenicals < As 5+
< As 3+ < arsine gas (AsH 3
).
Like mercury, trivalent arsenic compounds form covalent
bonds with sulfhydryl groups. The pyruvate dehydrogenase system
is particularly sensitive to inhibition by trivalent arsenicals
because the two sulfhydryl groups of lipoic acid react with arsenic
to form a six-membered ring. Inorganic arsenate (pentavalent)
inhibits the electron transport chain. It is thought that arsenate competitively
substitutes for phosphate during the formation of adenosine
triphosphate, forming an unstable arsenate ester that is rapidly
hydrolyzed.
Absorption, Distribution, Biotransformation, and Excretion. The
absorption of arsenic compounds is directly related to their solubility.
Poorly water-soluble forms such as arsenic sulfide, lead arsenate,
and arsenic trioxide are not well absorbed. Water-soluble arsenic
compounds are readily absorbed from both inhalation and ingestion.
GI absorption of arsenic dissolved in drinking water is >90%
(ATSDR, 2007a).
At low doses, arsenic is fairly evenly distributed throughout
the tissues of the body. Nails and hair, due to their high sulfhydryl content,
exhibit high concentrations of arsenic. After an acute high dose
of arsenic (i.e., fatal poisoning), arsenic is preferentially deposited in
the liver and, to a lesser extent, kidney, with elevated levels also
observed in the muscle, heart, spleen, pancreas, lungs, and cerebellum.
Arsenic readily crosses the placenta and blood-brain barrier.
Arsenic undergoes biotransformation in humans and animals
(Figure 67–9). Trivalent compounds can be oxidized back to pentavalent
compounds, but there is no evidence for demethylation of methylated
arsenicals. Biotransformation of arsenic varies greatly across
species, with humans excreting much higher levels of monomethylarsenic
(MMA) compounds than most other animals (ATSDR, 2007a).
Because the pentavalent methylated arsenic compounds have greatly
reduced toxicity, the methylation pathway was long thought to be a
detoxification pathway. However, the trivalent methylated arsenicals
actually are more toxic than inorganic arsenite, due to an increased
affinity for sulfhydryl groups, and formation of MMA III now is considered
a bioactivation pathway (Aposhian and Aposhian, 2006).
Elimination of arsenicals by humans primarily is in the urine,
although some is also excreted in feces, sweat, hair, nails, skin, and
exhaled air. Compared to most other toxic metals, arsenic is excreted
quickly, with a t 1/2
of 1-3 days. In humans, ingested inorganic arsenic
in urine is a mixture of 10-30% inorganic arsenicals, 10-20%
monomethylated forms, and 60-80% dimethylated forms.
Health Effects. With the exception of arsine gas (which
is discussed later in “Arsine Gas”), the various forms
of inorganic arsenic exhibit similar toxic effects.
Inorganic arsenic exhibits a broad range of toxicities
and has been associated with effects on every organ system
tested, although some systems are much more sensitive
than others (ATSDR, 2007a). Humans also are
exposed to large organic arsenic compounds in fish,
which are relatively nontoxic. Humans are the most
sensitive species to the toxic effects of inorganic
arsenic. Acute exposure to large doses of arsenic (>70-
180 mg) often is fatal. Death immediately following
arsenic poisoning typically is the result of its effects on
the heart and GI tract. Death sometimes occurs later as
a result of arsenic’s combined effect on multiple organs.
Cardiovascular System. Acute and chronic arsenic exposure
cause myocardial depolarization, cardiac arrhythmias,
and ischemic heart disease; these are known
side effects of arsenic trioxide for the treatment of
leukemia. Chronic exposure to arsenic causes peripheral
vascular disease, the most dramatic example of
which is “blackfoot disease,” a condition characterized
by cyanosis of the extremities, particularly the feet,
progressing to gangrene. Blackfoot disease is endemic
in regions of Taiwan, with arsenic levels of between 170
and 800 μg/L. Arsenic dilates capillaries and increases
their permeability. This causes edema after acute exposures
and is likely responsible for peripheral vascular
disease following chronic exposure.
O – GSH GSSG O – SAM SAH O – GSH GSSG O – SAM SAH O –
O As O – – O As O – O As
–
CH 3 O As CH3 O As CH 3
AS3MT
1869
CHAPTER 67
ENVIRONMENTAL TOXICOLOGY: CARCINOGENS AND HEAVY METALS
O – O – CH 3
Arsenate V Arsenite III MMA V MMA III DMA V
Figure 67–9. Metabolism of arsenic. GSH, reduced glutathione; GSSG, oxidized glutathione; SAM, S-adenosyl-L-methionine; SAH,
S-adenosyl-L-homocysteine. AS3MT, arsenite methyltransferase; MMA V , monomethylarsonic acid; MMA III , monomethylarsonous
acid; DMA V , dimethyl arsinic acid.