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

1860 Carcinogenicity. The primary concern with human exposure
to aflatoxins is the development of liver cancer.
Based on increased incidence of hepatocellular carcinoma
in humans exposed to aflatoxin and supporting
animal data, IARC has classified aflatoxin B 1
and several
other natural aflatoxins as known human carcinogens
(group 1) (IARC, 2002). Aflatoxin exposure and
hepatitis B virus work synergistically to cause hepatocellular
carcinoma. Many of the regions with elevated
aflatoxin exposure also have a high level of endemic
hepatitis B infection. Separately, aflatoxin or hepatitis
B exposure increases the risk of hepatocellular carcinoma
3.4- or 7.3-fold, respectively; those exposed to
both have a 59-fold increased risk of cancer compared
to unexposed individuals (Groopman et al., 2005).
SECTION IX
SPECIAL SYSTEMS PHARMACOLOGY
The mechanism of aflatoxin carcinogenesis has been extensively
studied (IARC, 2002). The 8,9-epoxide of aflatoxin B 1
readily
reacts with amines in biological macromolecules. Aflatoxin B 1
8,9-epoxide forms adducts with deoxyguanosine and albumin that
can be detected in the blood or urine of humans and laboratory animals
exposed to aflatoxin, providing evidence for the activity of
this pathway in vivo. Aflatoxin primarily forms DNA adducts at
deoxyguanosine residues, reacting at either the N1 or N7 position.
The N7-guanine adduct mispairs with adenine, leading to G l T
transversions. Human aflatoxin exposure is associated with hepatocellular
carcinomas bearing an AGG to AGT mutation in codon
249 of the p53 tumor suppressor gene, resulting in the replacement
of an arginine with cysteine. This mutation is almost never
observed in geographical regions with limited aflatoxin exposure
(Hussain et al., 2007).
The interaction between aflatoxin and hepatitis B that is
responsible for the increased incidence of hepatocellular carcinoma
is not well understood (Sylla et al., 1999). Hepatitis B influences the
metabolism of aflatoxin B 1
by upregulating CYPs, including 3A4,
and decreasing glutathione S-transferase activity. In addition, hepatocellular
proliferation to repair damage done by hepatitis B infection
increases the likelihood that aflatoxin-induced DNA adducts will
cause mutations. The hepatotoxic and tumor-promoting effects of
hepatitis B also could provide a more favorable environment for the
proliferation and invasion of initiated cells.
Chemoprevention of Aflatoxin-Induced Hepatocellular
Carcinoma. The clear relationship between aflatoxin
metabolism and its carcinogenicity makes it an appealing
target for chemopreventive strategies that modify its
metabolism (Groopman et al., 2008; Kensler et al.,
2004). Inhibiting CYP activity or increasing glutathione
conjugation will reduce the intracellular concentration
of the 8,9-epoxide and thus prevent DNA adduct formation.
One drug that has been tested as a modifier of
aflatoxin metabolism is oltipraz. Oltipraz is an antischistosomal
drug that potently inhibits CYPs and
induces genes regulated by the ARE. In a phase 2 clinical
trial, a 125-mg/day dose of oltipraz increased the
excretion of aflatoxin N-acetylcysteine, indicating
enhanced glutathione conjugation of the epoxide. At
500 mg/wk, oltipraz reduced the levels of aflatoxin M 1
,
consistent with inhibition of CYP activity.
Green tea polyphenols also have been used to modify aflatoxin
metabolism in exposed human populations. Individuals receiving
a daily dose of 500 or 1000 mg (equivalent to 1 or 2 L of green
tea) demonstrated a small decline in the formation of aflatoxin–
albumin adducts and a large increase in the excretion of aflatoxin N-
acetylcysteine, consistent with a protective effect. A third approach to
modifying aflatoxin metabolism has been to use a broccoli sprout
tea containing high levels of the isothiocyanate R-sulforaphane.
Because of interindividual variation in the absorption of R-sulforaphane,
the protocol did not significantly alter aflatoxin biomarkers. However,
there was a significant inverse correlation between excretion of sulforaphane
metabolites in the urine and the levels of aflatoxin–N7-guanine
adducts.
Yet another approach used for the chemoprevention of aflatoxin
hepatocarcinogenesis is the use of “interceptor molecules.”
Chlorophyllin, an over-the-counter mixture of water-soluble chlorophyll
salts, binds tightly to aflatoxin in the GI tract, forming a complex
that is not absorbed. In vitro, chlorophyllin inhibits CYP
activity and acts as an antioxidant. Oral doses are poorly absorbed
in vivo, so the agent remains largely in the GI tract. In a phase 2
trial, administration of 100 mg of chlorophyllin with each meal
reduced aflatoxin–N7-guanine adduct levels in the urine by >50%
(Egner et al., 2001).
Chemoprevention of hepatocellular carcinoma in people
exposed to aflatoxin also can be achieved by limiting infections with
hepatitis B. Because of the strong interaction between hepatitis B
and aflatoxin in carcinogenesis, the hepatitis B vaccine will reduce
the sensitivity of people to the induction of cancer by aflatoxin.
Primary prevention of aflatoxin exposure through hand or fluorescent
sorting of crops to remove those with fungal contamination can
also reduce human exposure. A more cost-effective primary prevention
approach is to improve food storage to limit the spread of A.
flavus, which requires a warm and humid environment.
METALS
Metals are an important class of environmental toxicantsl;
they are ubiquitous environmental contaminants
that come from both natural and anthropogenic sources.
Various toxic metals play important roles in many industrial
processes and are occupational health hazards and
common pollutants. The top three substances of concern
due to their toxicity and likelihood of human exposure
as listed under the Comprehensive Environmental
Response, Compensation, and Liability Act (CERCLA,
also known as Superfund) are arsenic, lead, and mercury.
The toxic effects of these three metals have played
a central role in the development of the field of toxicology.
However, the toxic effects of low-dose chronic
exposure to metals have only recently been appreciated.