Chemistry Reference
In-Depth Information
Although the liver is predominantly responsible for biotransformation of ingested
compounds, as it contains the majority of the XME, the colon and other tissues also
show activity (Helsby et al., 2000).
There are 57 CYPs encoded in the human genome, mainly catalyzing the
metabolism of steroids, bile acids, eicosanoids, drugs, and xenobiotic chemicals
(Guengerich, 2003). However, some of the P450s are also active carcinogens. Some
epidemiological research has shown increased risk of colon cancer in individuals
with high P4501A2 activity. The metabolic activation of food-borne heterocyclic
amines to colon carcinogens in humans is hypothesized to occur via N-oxidation
followed by O-acetylation to form the
N
-acetoxy arylamine that binds to DNA to
yield carcinogen-DNA adducts. These steps are catalyzed by hepatic cytochrome
P4501A2 and acetyltransferase-2 (NAT-2), respectively (Lang et al., 1994). It has
been postulated that probiotics, such as
Bifidobacterium,
could lower the risks of
colon cancer, by producing metabolites that could affect the mixed-function of
P450s and subsequently affect the conversion of azoxymethane from proximate to
ultimate carcinogen (Campbell and Hayes., 1976). These properties of probiotics
to alter the xenobiotic metabolizing enzyme suggest that probiotics could suppress
colon cancer.
Similarly, Helsby et al. (2000) showed that wheat bran fed at 10 or 20 percent
dietary levels to Wistar rats led to changes in the levels of activity and expression of
several XMEs, both in hepatic and colonic tissues. Other authors have shown dif-
ferential effects of wheat bran, carrot fiber, and oat bran, to suggest that the nature
or source of the dietary fiber influences which, if any, enzyme activities are modified
(Nugon-Baudon et al., 1996). However, the extent to which bacterial modification is
associated with these changes in expression of XMEs is not always clear. There are
at least two possible mechanisms by which prebiotics may affect hepatic or colonic
XMEs through actions on the microbiota (Ferguson et al., 2005; Kirlin et al., 1999).
Digestion and fermentation of dietary fiber carbohydrates leads to the production
of short-chain fatty acids, of which butyrate in particular has been shown to induce
phase 2 enzymes. Other authors (Ferguson et al., 2005; Helsby et al., 2000) have also
pointed out that the action of colonic esterases may lead to the release of hydroxycin-
namic acids from certain dietary fibers in the human colon, and these acids also have
modulatory effects on XMEs in mammalian cells.
Binding of carcinogens to bacterial cell walls has been suggested to protect
against colorectal cancer. El-Nezami and colleagues (El-Nezami et al., 1998; Eaton
and Gallagher, 1994; Henry et al., 1999) demonstrated such binding with aflatoxin B1
(AFB1), a fungal dietary contaminant causing mutagenic and carcinogenic effects in
both animals and humans. Binding of AFB1 was strain-specific, with
Lactobacillus
rhamnosus
strain GG (LBGG) and
L. rhamnosus
strain LC-705 (LC-705) the most
effective.
In vivo
, health benefits would work through preventing intestinal contact
and absorption, hepatic metabolism, and enhancing excretion.
In considering the case of AFB1 as an example, the physical sequestration of
the carcinogen has been implicated as the main mechanism for the reduced contact
and absorption into the intestinal mucosa and metabolic transformation by the liver
into mutagenic and carcinogenic metabolites. It was clearly shown that the effect
