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4.5.2 Modulation of the effects of aflatoxin with chemopreventive agents
The understanding of human metabolism of aflatoxin B 1 (see Section 4.1) and the
extensive literature on chemoprevention of aflatoxin B 1-induced carcinogenesis in
experimental animals have provided a rationale for chemoprevention studies in human
populations (Kensler et al., 1999). Notably, agents that induce hepatic GST and aflatoxin
aldehyde reductase (AFAR) in rats give rise to decreased aflatoxin–DNA and –protein
adduct formation and inhibition of aflatoxin-associated carcinogenicity (Roebuck et al.,
1991; Groopman et al., 1992; Judah et al., 1993; Kensler et al., 1997; Groopman &
Kensler, 1999). Consequently, a similar modulation of the balance between aflatoxin
activation and detoxification in humans has been sought and two chemopreventive
agents, oltipraz and chlorophyllin, have been evaluated in clinical trials in China.
The protective action of oltipraz is based on inhibition of the enzyme CYP1A2,
resulting in reduced formation of the aflatoxin B 1 8,9-epoxide and aflatoxin M 1, and
induction of GST enzymes, resulting in increased excretion of the 8,9-epoxide glutathione
conjugate as a mercapturic acid (Morel et al., 1993; Langouët et al., 1995). In
Chinese subjects exposed to aflatoxin through consumption of their regular diet,
concurrent dietary intake of oltipraz was shown to modulate aflatoxin metabolism by
increasing excretion of the mercapturic acid and decreasing urinary aflatoxin M 1 concentrations
and blood aflatoxin–albumin levels (Jacobson et al., 1997; Kensler et al., 1998;
Wang et al., 1999a).
Chlorophyllin is an anti-mutagen in genotoxicity assays in vitro and in vivo
(Dashwood et al., 1998). Mechanistic studies of aflatoxin B 1-induced hepatocarcinogenesis
in rainbow trout have revealed that chlorophyllin acts as an ‘interceptor molecule’
through the formation of tight molecular complexes with aflatoxin B 1 (Breinholt
et al., 1995). Consequently, it may diminish the bioavailability of aflatoxin B 1, leading
to reduced DNA-adduct formation and tumour development (Breinholt et al., 1999).
Chlorophyllin has also been evaluated in a chemoprevention trial in China and consumption
of 100 mg of this compound at each meal during four months led to an overall
reduction of 55% (p = 0.036) in median urinary concentrations of AFB 1−N7-Gua compared
with placebo controls (Egner et al., 2001).
The above clinical trials confirm that aflatoxin metabolism occurring in people
exposed to the toxin through the diet is consistent with the metabolic pathways deduced
from in vitro and animal model studies. These trials also provide proof of principle that
aflatoxin metabolism can be modulated in vivo to reduce genotoxic damage; this
provides a basis for prevention strategies through dietary modulation.
4.5.3 Interactions of hepatitis B virus and aflatoxins
AFLATOXINS 243
In countries with a high incidence of HCC, endemic infection with HBV is often
associated with exposure to aflatoxins. Prospective cohort studies from Asia have
observed a multiplicative increase in risk for HCC in individuals chronically infected
with HBV and exposed to dietary aflatoxins (see Section 2). Experimental studies in