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

termination of the trial (William et al., 2009). Studies
examining long-term treatment with aspirin for cardiovascular
benefits found that aspirin also reduces the
incidence of colorectal adenomas. A phase 3 clinical
trial is under way to examine this effect. Natural compounds,
such as -tocopherol, also can exert chemoprevention
by reducing inflammation.
One successful approach to chemoprevention is modification
of nuclear receptor signaling. Promising preliminary data suggested
that retinoids might be beneficial for preventing lung and other cancers.
Retinoids reduce the incidence of head and neck cancers, which
represented one of the first successful uses of chemoprevention in
humans (William et al., 2009; Evans and Kaye, 1999). Retinoids also
are effective for the treatment of acute promyelocytic leukemia (see
Section VII). However, in large clinical trials, retinoids actually
increased the incidence of lung cancer, particularly among women,
and had other unacceptable toxicities (Omenn et al., 1996).
The selective ER modulators tamoxifen and raloxifene reduced
the incidence of breast cancer in high-risk women in large phase
3 clinical trials and are approved for chemoprevention in these patients
(Vogel et al., 2006). The success of selective estrogen-receptor modulators
for chemoprevention provides a proof-of-principle that the
development of compounds based on mechanistic predictions can lead
to effective drugs for the prevention of cancer.
Aflatoxin B 1
. Promising agents are being developed as
chemopreventants of hepatocarcinogenesis mediated by
aflatoxin B 1
. Aflatoxins are produced by Aspergillus
flavus, a fungus that is a common contaminant of
foods, especially corn, peanuts, cottonseed, and tree nuts.
A. flavus
in food
Primary
Prevention
Chlorophyllin
Absorption
O
Hydroxylated
metabolites (detox)
H
CYPs
1A2, 3A4
O
H
O
O
Aflatoxin B 1
in liver
O
O
Oltipraz,
GTPs, ITCs
CH 3
CYPs
1A2, 3A4
A. flavus is abundant in regions with hot and wet climates,
and as a result, hepatocellular carcinoma is a serious
problem in subtropical and tropical regions of Latin
America, Africa, and Southeast Asia. Human exposure
to aflatoxin in the U.S. is very rare and not thought to
have a significant impact on health (IARC, 2002).
Absorption, Distribution, Biotransformation, and Excretion.
Aflatoxin B 1
is readily absorbed from the GI tract and initially distributed
to the liver, where it undergoes extensive first-pass metabolism
(Guengerich et al., 1996). Aflatoxin B 1
is metabolized by
CYPs, including 1A2 and 3A4, to yield either an 8.9-epoxide or
products hydroxylated at the 9 position (aflatoxin M 1
) or 3 position
(aflatoxin Q 1
; Figure 67–3). The hydroxylation products are less susceptible
to epoxidation and are therefore detoxification products.
The 8,9-epoxide is highly reactive toward DNA and is the reactive
intermediate responsible for aflatoxin carcinogenesis. The 8,9-epoxide
is short lived and undergoes detoxification via non-enzymatic
hydrolysis or conjugation with GSH. Aflatoxin M 1
enters the circulation
and is excreted in urine and milk. Hydroxylated aflatoxin
metabolites also can undergo several additional phase 1 and phase 2
metabolic pathways prior to excretion in urine or bile.
Toxicity. Aflatoxin B 1
primarily targets the liver, although it also is
toxic to the GI tract and hematological system. High-dose exposures
result in acute necrosis of the liver, leading to jaundice and, in many
cases, death. Acute toxicity from aflatoxin is relatively rare in humans
and requires consumption of milligram quantities of aflatoxin per day
for multiple weeks. An outbreak in Kenya in 2004 led to 317 cases
and 125 deaths (Groopman et al., 2008). Humans seem to be relatively
resistant to acute aflatoxicosis; human outbreaks usually are preceded
by the deaths of dogs and other domestic animals. Chronic exposure
to aflatoxins results in cirrhosis of the liver and immunosuppression.
O
O
GSH
conjugates (detox)
O
Albumin
GSTs
O
O
GSH
O
Aflatoxin B 1
epoxide
O
CH3
DNA
N-acetylcysteine
conjugates
DNA Adducts
1859
CHAPTER 67
ENVIRONMENTAL TOXICOLOGY: CARCINOGENS AND HEAVY METALS
Albumin
adducts
Figure 67–3. Metabolism and actions of aflatoxin B 1
. Following absorption, aflatoxin B 1
undergoes activation by CYPs to its 8,9-epoxide,
which can be detoxified by glutathione S-transferases (GSTs) or by spontaneous hydration. Alternatively, it can react with cellular
macromolecules such as DNA and protein, leading to toxicity and cancer. Oltipraz, green tea polyphenols (GTPs), and isothiocyanates
(ITCs) decrease aflatoxin carcinogenesis by inhibiting the CYPs involved in activating aflatoxin and increasing the synthesis of the
cofactor GSH for GSTs involved in detoxification.