Professional Documents
Culture Documents
effects
on cytochromes
P450,
xenobiotic
metabolism,
and toxicity
CHUNG
S. YANG,
JOHN
F. BRADY,2
AND
HONG
JUN-YAN
Laboratory
ABSTRACT
The levels
and activities
of cytochrome
P450 enzymes
are influenced
by a variety
of factors,
including
the diet. In this article, the effects of selected
nonnutritive
dietary
chemicals,
macronutrients,
micronutrients, and ethanol
on cytochromes
P450 and xenobiotic
metabolism
are reviewed
in the light of our current
understanding
of the multiplicity
and substrate
specificity
of cytochrome
P450 enzymes.
Although
the mechanisms
of action
of several
dietary
chemicals
on specific
cytochrome
P450 isozymes
have been established,
those for
macroand micronutrients
are largely
unknown.
It is
known,
however,
that specific
nutrients
may have varied
effects on different
cytochrome
P450 forms and thus may
affect the metabolism
of various
drugs differently.
Nutritional deficiencies
generally
cause lowered
rates of xenobiotic metabolism.
In certain
cases, such as thiamin
deficiency and mild riboflavin
deficiency,
however,
enhanced
rates of metabolism
of xenobiotics
were observed.
The
effects of dietary modulation
of xenobiotic
metabolism
on
chemical
toxicity
and
carcinogenicity
are discussed.
-Yang,
C. S.; Brady, J. F.; Hong,
-Y. Dietary
effects on
cytochromes
P450,
xenobiotic
metabolism,
and toxicity.
FASEBJ.
6: 737-744;
1992.
J.
Key Words:
diet
tion
xenobiotics
nutrition
cytochromes P450 . enzyme
drug metabolism . toxicity . carcinogens
regula-
CLOSE RELATIONSHIP
BETWEEN
DIET and xenobiotic
metabolism
may be traced back to prehistoric
days in animalplant warfare during evolution
(1). Plants synthesized
chemicals
for self-protection
and
animals
had
to develop
xenobiotic-metabolizing
enzymes
such as cytochrome
P450
(P450)3 for the detoxication
of these chemicals.
The evolution of the large number
of P450 2 genes 400 million years
ago may correspond
to the advance
of animals
onto land
where they encountered
new terrestrial
plants
and phytochemicals.
The work of many investigators
in the past 30
years has clearly established
that various dietary
factors have
marked
effects on the metabolism
of drugs,
environmental
chemicals,
and certain endogenous
substrates.
This topic has
been reviewed extensively
(2-9). However, only recently
have
we begun to understand
some of these effects at the molecular level. Dietary
influences
on xenobiotic
metabolism
may
alter the therapeutic
effects of drugs and the toxicity or carcinogenicity
of environmental
chemicals.
In this article,
we
review
the mechanisms
by which
dietary
chemicals
and
nutritional
status affect the levels and activities
of P450 enzymes, xenobiotic
metabolism,
as well as chemical
toxicity
and carcinogenicity.
Because
of space
limitations,
we have chosen
to use
selected
examples
to illustrate
key concepts
rather
than to
conduct
an exhaustive
review on this topic. Review articles
are cited instead
of original
papers.
THE
non,
o/o,/nnne.
n7l7Icnl
en
Th
and
MODULATION
METABOLISM
CHEMICALS
Pharmacognosy,
College
OF P450 LEVELS
BY NONNUTRITIVE
of Pharmacy,
AND
XENOBIOTIC
DIETARY
Dietary
chemicals
may affect the levels and activities
of P450
at different
steps as shown in Fig. 1. Dietary
chemicals may affect the levels of P450 species by altering
the rates
of: 1) the transcription
of specific P450 genes, 2) the degradation
of specific
mRNA,
3) the translation
process,
and
4) P450 degradation
through
protein
turnover
or by suicide
inhibition.
Many
dietary
chemicals
are substrates
of the
P450-dependent
monooxygenase
system.
They or their metabolites
may inhibit or enhance
the activities
of this system
by binding
to P450 species or to NADPH:P450
reductase,
by
affecting the interaction
between
these enzymes,
or by affecting key steps in the catalytic
cycle.
isozymes
Induction
of P450-dependent
activities
The
To whom correspondence
should be addressed,
at: Laboratory
for Cancer Research, Department
of Chemical Biology and Pharmacognosy, College of Pharmacy,
Rutgers University,
Piscataway,
NJ 08855-0789, USA.
2Present address: Chemistry
Department,
University of California, Davis, CA95616, USA.
3Abbreviations:
P450(s), cytochromes P450; BP, benzo(a)pyrene;
Ah receptor, aromatic hydrocarbon
receptor; RXM, acid reaction
products
of indole-3-carbinol;
NDMA,
N-nitrosodimethylamine;
NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone;
BHA, butylated hydroxyanisole;
B HT, butylated hydroxytoluene.
II
III
III
P450
gene
transcription
P450 mRNA
degradation
translation
degradation
P450
.(
Inactivation
Reductase
Substrates
Inhibiton
Enhancement
738
Vol. 6
lanuarv
1992
Inactivation
of P450
enzymes
of monooxygenase
activities
Flavone,
tangeretin,
and nobiletin
were found to increase
BP
hydroxylase
activity
and aflatoxin
B, activation
in human
liver microsomes
(4). The metabolism
of antipyrine
and
zoxazolamine
was also stimulated,
but that of hexobarbital,
coumarin,
and 7-ethoxycoumarin
was not. The stimulatory
effect was P450 isozyme-specific.
With purified
P450 isozymes in a reconstituted
system, the effect was observed
with
rabbit P450s 3A6 and 1A2 but not with P450s 2B4, 2C3, or
1AI.
It was proposed
that these flavonoids
stimulate
the
monooxygenase
activity
by enhancing
the interactions
be-
cxc
JCH.OK
IndoI.3.c,anoI
Indo{.5.b)ca.bae1.
CH,CH.N #{149}
C - S
DM oISd
Phneth1
SotSocyaSai.
OCH.
c)OO\ cX0
cOOk
PS
Flavone
Quercebn
Figure
The FASEBJournal
2. Structures
Tange,otin
Nob,I.bn
Kaenpfeoi
of some dietary
or related
compounds.
YANC FT At
of monooxygenase
activities
Dietary
compounds
can bind to the active sites of P450 enzymes,
serving
as substrates
or competitive
inhibitors.
For
example,
diallyl
sulfide
and phenethyl
isothiocyanate
are
competitive
inhibitors
of P450 2El-catalyzed
reactions (20, 21).
In addition,
phenethyl
isothiocyanate
also competitively
inhibits the metabolism
of 4-(methylnitrosamino)-1-(3-pyridyl)-1butanone
(NNK),
a potent tobacco carcinogen,
in lung microsomes (23). In this case, a purely competitive
mode of inhibition was not observed,
possibly due to the inactivation
of the
enzyme during the incubation,
and P450 2El was not involved.
Many dietary flavonoids
have been shown to inhibit monooxygenase
activities.
For example,
quercetin,
kaempferol,
morin,
and chrysin inhibited
BP hydroxylase
activity in human
liver microsomes
(4). Quercetin,
kaempferol,
and
naringenin
inhibited
nifedipen
and filodipen
oxidation
catalyzed by P450 3A4 in human
microsomes
(24). It appears
that flavones having
free hydroxy
groups on the A ring are
inhibitors,
whereas
flavonoids
containing
no hydroxy
groups
(flavone,
tangeretin,
and nobiletin)
are activators
(stimulators) of selected
monooxygenase
activities.
EFFECTS
OF MACRONUTRIENTS
METABOLISM
ON
XENOBIOTIC
Compared
with the effects of nonnutritive
dietary chemicals,
the effects of macronutrients
on drug metabolism
are more
difficult
to understand.
In the former
case, the actions of a
compound
or its metabolites
can be studied,
but in the latter
case we have to deal with a nutritional
state or status. Therefore, despite
extensive
investigations,
our understanding
of
the latter subject is mostly at the descriptive
level. Only recently have researchers
begun to look at specific changes
on
selected
enzymes
and the molecular
mechanisms
involved.
Many previously
seemingly
contradictory
results may be interpretable
based on our new knowledge
on P450 isozymes.
A dietary
manipulation
of nutritional
status may increase
the levels of a certain
group of P450s but decrease
those of
others.
Therefore,
depending
on the substrates
used in the
study, opposite
effects on drug metabolism
may be observed.
Protein
Diets with low protein
content
or lower quality
of protein
usually
result in lower rates of xenobiotic
metabolism
than
a normal
diet. This effect was observed
in human
volunteers
concerning
the metabolism
of antipyrine
and theophylline
(2, 4) and in animals
with a variety of xenobiotics
(25). The
P450 enzymes
may be affected
because
protein
synthesis
is
retarded
under protein
deficiency
conditions.
However,
the
effect on xenobiotic
metabolism
may be observed even without
common
signs of nutritional
protein
deficiency.
It is possible
that dietary
protein
level influences
the physiological
state,
such as hormone
levels, which affect the level of P450 enzymes.
Lipid
and
carbohydrate
In comparison
to a fat-free
diet, feeding
a 3-10% corn oil
diet to rats caused an increase in the microsomal
metabolism
of a variety
of substrates,
including
aminopyrine,
ethyl-
fllrrAPv
crrrrc
rmi
vrMr,o,cyr,r
.ACTAPCI
ICkA
morphine,
hexobarbital,
heptachlor,
BP, NDMA,
and aniline
(8, 26, 27). Generally,
fat levels are important
in affecting
P450 levels, and those rich in polyunsaturated
fatty acids are
more effective than those rich in saturated
and monounsaturated fatty acids. Dietary
lipids are also essential
in producing an optimal
induction
of P450 enzymes
by inducers
such
as phenobarbital,
and the effect is observable
at the mRNA
level (27). Although
most studies suggested
that the factors
responsible
for the increased
drug metabolism
were lipids,
the lipid-to-carbohydrate
ratio may be important.
Other
components
or contaminants
in oils such as vitamin
E, cholesterol, and lipid peroxides
may have also been contributing
factors in certain
experiments
(26).
Recent results from our laboratory
indicate
that, in comparison
to a fat-free
diet, a 20% corn oil diet produced
a
twofold
higher
constitutive
level of P450 2E1 but did not
affect the maximal
acetone-inducible
level of this enzyme
(27). When
diets containing
different
amounts
of corn oil
were fed to rats, those on the higher fat diet had higher P450
2E1 levels and higher
blood acetone
levels (27), consistent
with the hypothesis
that ketone bodies and ketosis are key
factors
for the regulation
of P450 2E1 (28). Menhaden
oil
and corn oil were more effective
than olive oil and lard in
maintaining
high levels of P450 2E1, suggesting
that factors
other than ketosis were involved.
The total concentration
of
microsomal
P450 was higher
in rats on a diet with higher
lipid content;
specifically,
P450s 3A and 2A1 were higher,
whereas
2B1 and 2C11 were not affected
(29).
Carbohydrates
are usually
used as variable
caloric sources
for isocaloric
diets in studying the effects of dietary
proteins
or lipids on xenobiotic
metabolism.
The higher
P450 levels
observed
with higher protein or lipid diets have usually been
attributed
to the protein
or lipids. However,
metabolic
glucose deprivation,
seen in cases of fasting
and diabetes,
caused
induction
of P450 2E1, possibly
due to the ketotic
conditions
produced.
Sucrose,
glucose,
or fructose,
when
given in drinking
water to mice maintained
on a rodent chow,
were reported
to decrease
drug metabolism
rates in vivo and
in vitro (30). The high sugar intake from the drinking
water
may have reduced
the dietary
intake
of protein
(or other
nutrients)
that affected
monooxygenase
activities.
Alternatively, a high dietary
or blood glucose level may inhibit the
synthesis
of P450s due to inhibition
of y-aminolevulinic
acid
synthesis (31).
Fasting
and
dietary
restriction
During
fasting,
microsomal
aminopyrine
N-demethylase
and hexobarbital
hydroxylase
activities
were decreased,
but
aniline p-hydroxylase
and p-nitroanisole
O-demethylase
activities were increased
in male rats (32). The induction
of
P450 2E1 by fasting (17) can account
for the increased
aniline hydroxylase
and NDMA
demethylase
activities.
Fasting
for 2 or 3 days caused
a 50% decrease
in the level of the
male-specific
P450 2C11 (33), and this may account
for the
previously
observed
decrease
in aminopyrine
demethylase
activity.
During
fasting,
the mRNA
for P450 2E1 was significantly
elevated,
a situation
similar to diabetes
(34), but
such elevation
was not observed
during
the induction
of
P450 2E1 by acetone
pretreatment
(19). The results Suggest
that there are differences
in the mechanisms
of P450 2E1 induction
under these conditions.
In nutritional
studies
with experimental
animals,
pair
feeding is frequently
used to allow the animals
in the control
group eating a quantity
of diet equivalent
to that consumed
by animals in the experimental
group. If the pair-fed
animals
consume
this limited amount
of food in 2 h, usually early in
739
the
morning,
this
will
which increases
in P450
served (35). The practice
periment
may also cause
create
2E1
a fasting
and
its
of overnight
an increase
situation
activities
of 22 h in
can be ob-
chrome
c reductase
microsomal
ethoxycoumarin
hydroxylase
sumption
ALCOHOL
CONSUMPTION
METABOLISM
gus
ON
postulated
(36).
been
demonstrated
enzyme
catalyzes
drug
ethanol,
other alcohols,
NDMA,
acetone,
aniline,
enflurane,
ether, acetaminophen,
benzene,
chloroform,
carbon
tetrachloride,
dihaloethanes,
and other small halogenated
hydrocarbons
(Fig. 3) (40, 41). It is understandable,
therefore,
that
chronic
consumption
of ethanol
will increase
the rate of the
metabolism
and the toxicity
of the aforementioned
compounds.
On the other hand, the acute effect of alcohol consumption
is an inhibition
of P450 2E1 function
due to the
competitive
inhibition
by ethanol.
As reviewed
by Lieber
(36), chronic
administration
of
ethanol
increases
the rate of the metabolic
clearance
of a
variety
of
aminopyrine,
drugs
such
tolbutamide,
as
meprobamate,
propranolol,
pentobarbital,
rifampicin,
and
testosterone.
As a result
of acute
ethanol
consumption,
however,
impairment
of the metabolism
of drugs has been
observed
with meprobamate,
benzodiazepines,
phenothiazine, barbiturate,
morphine,
methadone,
warfarin,
xylene,
and other compounds.
The induction
and inhibition
of P450
2E1 may account
for only a small portion of these inhibitory
actions.
The induction
of other P450s such as P450 2B1 and
possible
inhibition
of the metabolism
of these drugs
by
ethanol
remain
to be studied.
Chronic
ethanol
administration
to rats caused a proliferation of the endoplasmic
reticulum
of the upper small intestine along with increases
in P450 content
and NADPH:cyto-
The
extent
The
Substrates
Acetone,Alcohols
Aniline, Pyridine
Benzene, Phenol, Styrene
Alkanes
CHCI3, Cd4
Vinyl chloride
Dihaloethanes
Trichloroethylene
N-Nitrosodimethylamine
N-Nitrosodiethylamine
Azoxymethane
t-Butylhydroperoxide
Ethers
Enflurane, Halothane
Chlorzoxazone
Acetaminophen
Figure 3. Dietary effectorsand substrates for P450 2E1.
Ianuarv
1992
Th
cAcIR
7-
and
aniline
ethanol
concontent
and the
P450
of N-nitrosopyrrolidine
these
intestinal
demethylase,
in
effects
are
due
rat
esophato the
in-
to be determined.
lung has also been
(19, 43).
EFFECTS
OF MICRONUTRIENTS
METABOLISM
effects
of vitamins,
metabolism
9). Seemingly
ON
especially
vitamin
XENOBIOTIC
deficiencies,
on
(2,
5, 8,
may be
more understandable
with some new insights
on this topic.
1) Whereas
a general effect of all severe vitamin
deficiencies
is the decreased
metabolic
functions
and lowered
levels of
P450-dependent
metabolic
activities, mild deficiency
in a
certain
nutrient
may enhance
P450-dependent
activities.
Therefore,
depending
on the severity of the deficiency,
opposite effects on xenobiotic
metabolism
may be observed.
2) Deficiency
in a single nutrient
may produce
varied effects
on the metabolism
of different
xenobiotics
due to the different effects on specific P450 isozymes.
These
points
are illustrated
in the
During
a gradual
possibly
cases
of riboflavin
and
thiamin
deficiencies.
the development
of riboflavin
deficiency,
decrease
in the activity of NADPH:P450
due
to the
lowered
levels
of cellular
FAD
there was
reductase,
and
FMN.
reductase
Vol. 6
to increase
to which
Rats
fed a thiamin-deficient
tions
of P450,
cytochrome
740
increased
duction
of P450 2E1 or its activity
remains
The induction
of P450 2E1 in kidney
and
observed
induction
in animals
the metabolism
In addition,
benzphetamine
deethylase,
BP hydroxylase,
have been observed (36). Chronic
activation
(42).
Consumption
of alcoholic
beverages
is widespread
and can
account
for a significant
portion
of caloric intake of certain
individuals.
Ethanol
can affect the absorption,
plasma
protein binding,
blood flow, and distribution
of xenobiotics
as
well as have profound
influence
on phase I and phase II
metabolism
of xenobiotics (36, 37).
The induction
of P450 enzymes
by ethanol
has long been
The
of
metabolic
EFFECT
OF
XENOBIOTIC
activity.
activities
activity
in liver
diet
b5, and
microsomes
had
higher
concentra-
NADPH:cytochrome
than
those
fed
c
a diet
sufficient
in thiamin.
The deficient
rats also had increased
rates in the metabolism
of acetaminophen,
NDMA,
aminopyrine,
ethylmorphine,
zoxazolamine,
heptachlor,
aniline,
N-methylaniline,
acetanilide,
and BP, but not in the metabolism of hexobarbital
(8). Recent studies from our laboratory
indicated
that thiamin
deficiency
increased
the hepatic microsomal P450 2E1 level (two- to fivefold) but not the P450 2Cll
level (44). This observation
provides
an enzymatic
basis for
the enhanced
rate of in vivo metabolism
of aniline,
NDMA,
and acetaminophen,
all of which are substrates
for P450 2El.
Thiamin
deficiency
was shown to increase
cytosolic
glutathione S-transferase
activity moderately
but not steroid isomerase activity
(44). The mechanisms
of these effects on drugmetabolizing
enzymes
remain
to be elucidated.
Mechanistic
information
on the effects of other micronutrients
on xenobiotic
metabolism
is lacking.
These effects,
together
with the aforementioned
effects on xenobiotic
metabolism
by riboflavin
and thiamin
nutrition,
are summarized in Table 1.
In,
,n.I
VAklt
CT
Al
TABLE
1. Effects of micronutrients
on xenobiotic
metabolism
Xcnobiotic
Nutritional status
Vitamin
A deficiency
Vitamin
A-high
of aminopyrine,
I Metabolism
dose
of aniline,
Metabolism
Niacin deficiency
ethylmorphine,
7-ethoxycoumarin
of anesthetics
deficiency
Reductase
Mild
I Metabolism
Severe
of NDMA,
Metabolism
of BP,
deficiency
Vitamin
C deficiency
P450, reductase
Monooxygenase
activities
Vitamin
Monooxygenase
activities
Vitamin
E deficiency
Metabolism
cobalt,
heavy
metals-high
Calcium
deficiency
Magnesium
Induction
of codeine,
ethylmorphine,
aniline,
zoxazolamine,
acetanilide
BP
BP
dose
I Monooxygenase
ethylmorphine
activities
activities
I Monooxygenase
activities
I Metabolism of aniline, hexobarbital
deficiency
I Metabolism
of BP
Iron deficiency
I Metabolism
I Metabolism
of hexobarbital,
of aniline
Iron-large
dose
I NADPH-dependent
Selenium
deficiency
I Induction
Zinc deficiency
DIETARY
TOXICITY
N-methylaniline,
and other
deficiency
Abbreviations
found in reviews
b5
aminopyrine,
ethylmorphine,
I Hepatic P450
I Metabolism of p-nitrophenole,
high dose
aminopyrine
ethylmorphine,
high dose
aniline,
aminopyrine,
Thiamin
Copper
and enzymes
P450
Metabolism
Riboflavin
metabolism
I Metabolism
of pentobarbital,
I, decrease;
I, increase;
P450
2E1 AND
CHEMICAL
ON
lipid peroxidation
of P450 by phenobarbital
EFFECTS
reductase,
In this section,
P450 2E1 is used as an example
to illustrate
the dietary modulation
of P450 enzymes
and the effect of this
modulation
on toxicity and carcinogenicity
of chemicals.
As
illustrated
in Fig. 3, diet may provide
inducers,
suppressors,
inhibitors,
and substrates
for P450 2El. In addition
to affecting the hepatic microsomal
P450 2E1 level measured
in vitro,
a low fat/high
carbohydrate
diet also resulted
in a lower rate
of enflurane
metabolism
in rats than a high fat/low carbohydrate diet (29). Based on these results,
it may be suggested
that individuals
on a low fat diet may have, on average, lower
P450 2E1 levels than those on a high fat diet. Frequent
consumption
of ethanol is known to elevate the level of P450 2E1
in humans,
and is believed to be a key mechanism
for the enhanced
toxicity
of acetaminophen,
CCI,, and other chemicals. Fasting can be an important
factor in raising P450 2E1
levels in individuals
undergoing
weight reduction
by severe
fasting
or a low carbohydrate
diet. The induction
of P450
2E1 by fasting probably
also contributes
to the enhanced
toxicity of acetaminophen,
although
other
factors
such as
decreased
glutathione
levels are also important.
The activity of P450 2E1 is also modulated
by dietary inhibitors and suppressors
of this enzyme.
The consequence
of
this inhibition
and suppression
of P450 2E1 is the inhibition
of metabolism
and toxicity of certain
xenobiotics.
The inhi-
MFTAROI
1cM
aminopyrine
aminopyrine
NADPH:
P450 reductase
activity.
Original
references
can be
bition
of enflurane
metabolism
by diallyl
sulfide
and
phenethyl
isothiocyanate,
which are competitive
and suicide
inhibitors
of P450 2E1, has been demonstrated
in rats (unpublished
results).
The inhibition
of carcinogen
metabolism
in the liver can
increase
the carcinogen
exposure
to nonhepatic
organs and
thus may enhance
nonhepatic
carcinogenesis.
This effect has
been demonstrated
with ethanol,
which inhibited
hepatocarcinogenesis
of NDMA
but enhanced
tumorigenesis
in the
nasal cavity (45). The dual effects of ethanol,
i.e., an acute
effect of inhibition
and a chronic
effect of enhancement
of
NDMA-induced
carcinogenesis,
have also been observed (46).
Knowing
that many dietary factors can modulate
P450 2E1,
it may be questioned
whether
a higher or lower level of this
enzyme
is more beneficial
to health. A possible physiological
function
of P450 2E1 is in the initial step for the conversion
of acetone to glucose (47), but the rate of this metabolic
pathway is rather low and its physiological
importance
remains
to be established.
Lowering
P450 2E1 levels may thus decrease the susceptibility
to many toxic chemicals,
provided
the parent
compounds
are not toxic and can be disposed
of
by other metabolic
pathways
or by exhalation.
One exception
is the dihaloethanes,
which are activated
by a glutathionedependent
pathway
and detoxified
by P450 2E1-dependent
metabolism
(41). A second
aspect
of this question
is that
P450 2E1 is known to be effective in causing
lipid peroxidation (48). It remains
to be determined
whether
higher levels
741
DIETARY
EFFECTS
TOXICITY,
AND
ON
DRUG
METABOLISM,
CARCINOGENESIS
of cruciferous
vegetables
against
chemically
in the
trout,
the
inhibitory
action
of the
acid
reaction
products
of indole-3-carbinol
(RXM)
on the metabolic activation
of aflatoxin
B, may be a major mechanism
for the inhibition
of carcinogenesis
by indole-3-carbinol
(52).
On the other hand, when indole-3-carbinol
was given after
the aflatoxin
B, treatment
period, it enhanced
carcinogenesis
in the trout (53); the mechanisms
are not known.
It has also been demonstrated
that indole-3-carbinol,
when
incorporated
into the diet, increased
the estradiol
2-hydroxylase
activity
in rats and humans
(54), possibly due
to the induction
of P450s lAl and 1A2. Because
2-hydroxylation converts
estradiol
to nonuterotropic
and antiestrogenic
metabolites,
the increase
in this metabolic
activity
was suggested to reduce
the incidence
of estrogen-related
cancers.
Phenethyl
isothiocyanate
was a very potent
inhibitor
of
NNK-induced
lung tumorigenesis
(55) and N-nitrosomethylbenzylamine-induced
esophageal
carcinogenesis
(56). The
action can be attributed
largely to its inhibition
of carcinogen activation
(23). Probably
via a similar
mechanism,
diallyl sulfide was also an effective
inhibitor
in both carcinogenesis models (unpublished
results;
ref 57). Diallyl sulfide
and related
organosulfur
compounds
may be partially
responsible
for the negative
association
between
the consumption of allium vegetables
and incidence
of gastric cancer (58).
742
Vol. 6
January
1992
genesis
assays
in vitro,
may
be
of particular
importance.
It
is also important
to consider
the doses of these chemicals
required
to produce
the possible
harmful
effects. Depending
on the dose, a compound
can have either beneficial
or harmful effects, and sometimes
the effects depend
on the experimental
model used. This point can be illustrated
with the
commonly
used food additives,
butylated
hydroxyanisole
(BHA) and butylated
hydroxytoluene
(BHT).
These antioxidants
may
be present
at a total
concentration
of up to 0.02%
in certain food items. When added to the diet at a concentration of 0.5%, BHA and BHT
inhibited
carcinogenesis
in
several animal
models (59). Induction
of phase II enzymes
and inhibition
of carcinogen
activation
have been proposed
as the mechanisms
of inhibition
(8, 59). However,
with 1 or
2% of BHT or BHA in the diet, respectively,
tumor promotion activity
has been demonstrated
in a two-stage
urinary
bladder
carcinogenesis
model (60).
induced
carcinogenesis
in animals
and for the association
between
the frequent
consumption
of these vegetables
with lower
cancer incidences
at different
organ sites (51). The induction
of P450 1A1 in the intestine
may help to metabolize
and
eliminate
dietary
polyaromatic
hydrocarbons
in the intestine, and thus may reduce the exposure
of internal
organs to
such carcinogens.
In studies of aflatoxin
B1-induced
hepatocarcinogenesis
The amount
of diallyl sulfide derived
from garlic is only in
quantities
of 3-100 ftg/g. The estimated
human
intake
of
glucosinolates
through
consumption
of cooked vegetables
is
about 30 mg per day. It may be questioned
whether
such
small quantities
of dietary
inhibitors
can have a significant
effect in inhibiting
carcinogenesis.
Two aspects may be pertinent to this question:
1) Many dietary
compounds
may be
competitive
inhibitors
of P450 enzymes;
even when present
at low concentrations,
they could
effectively
inhibit
the
metabolism
of low concentrations
of carcinogens.
2) Many
dietary
chemicals
can inhibit
carcinogen
activation.
Although
most of them are present
only in small concentrations, in combination
their actions
can be significant.
The human diet is also known to contain
mutagens,
carcinogens, and tumor promoters.
The effects of these compounds
on health
have to be considered
in light of the capability
of the body to detoxify
these dietary
chemicals.
Phase II
metabolism,
which is usually
not considered
in most muta-
CONCLUDING
Studies
of the multiplicity
isozymes
effects
REMARKS
have
and
contributed
animals
the
level
to humans.
metabolism.
specificity
understanding
of certain
With
A dietary
of P450
of dietary
may inlevel of
others; thus the rates of the metabolism
of certain drugs may
be enhanced
and those of others lowered.
The distinction
between an inhibitory
effect after an acute dose and an induction effect after a treatment
also helps to explain
the divergent effects of dietary
chemicals
on drug metabolism.
In
addition,
a nutritional
deficiency
may have different
effects
on the metabolism
of a certain
drug; the rate may be enhanced
in mild deficiency
but decreased
in severe deficiency.
Most of the studies reviewed
herein were carried out using
liver microsomes
from rats and mice. These results can provide us with some basic understanding
of the mechanisms
by
which a dietary
factor may affect drug metabolism.
Caution
must be applied
when extrapolating
the information
obtained
from hepatic
tissues to nonhepatic
tissues and from
crease
on xenobiotic
substrate
to our
P450s
the
and
understanding
chemical
decrease
the
of human
xeno-
biotic metabolism
as a goal, researchers
are faced with the
following
challenges:
1) to further
elucidate
the detailed
mechanisms
by which diet affects xenobiotic-metabolizing
enzymes,
2) to understand
the basis for the tissue and species
specificities
of xenobiotic-metabolizing
enzymes,
3) to further
characterize
the catalytic
properties
of human
xenobioticmetabolizing
enzymes,
and 4) to pursue
well-planned
human
studies
concerning
the nutritional
impact
on drug
metabolism
and toxicity.
YANC
FT Al
the
assistance
and
Ms.
Marie
Leithauser
for helping
to pre-
manuscript.
REFERENCES
1. Nelson, D. R., and Strobel, H. W. (1987) Evolution
of cytochrome P-450 proteins. Mol. BioL Evol. 4, 572-593
2. Anderson, K. E., Pantuck, E. J, Conney, A. H., and Kappas,
A. (1985) Nutrient
regulation
of chemical metabolism
in humans. Federation Proc. 44, 130-133
3. Bidlack, W. R., Brown, R. C., and Mohan, C. (1986) Nutritional parameters
that alter hepatic
drug metabolism,
conjugation, and toxicity.
Federation Proc. 45, 142-148
4. Conney,
A. H. (1982) Induction
of microsomal
enzymes
by foreign
chemicals
and
carcinogenesis
by polycyclic
aromatic
hydrocarbons:
G. H. A. Clowes Memorial
Lecture.
Cancer Res.
42, 4875-4917
6. Guengerich,
processes
F. P. (1984) Effects
involving
bioactivation
Annu. Rev. Nutr. 4, 207-231
7. Hathcock, J. N. (1985) Metabolic
interactions.
Federation Proc. 44,
of nutritive
factors
and detoxication
mechanisms
of drug-nutrient
124-129
8. Yang, C. S., and Yoo, J. -S. H. (1988) Dietary
metabolism
Ther. 38,
by the
53-72
mixed-function
oxidase
on metabolic
of chemicals.
effects on drug
system.
Pharinacol.
P4501A1
and 5,6-benzoflavone.
Carcinogenesis 11, 1259-1263
12. Gillner, M., Bergman, J., Cambillau,
C., Fernstrom,
B., and
Gustafsson, J. - A. (1985) Interactions
of indoles with specific
binding
sites for 2,3,7,8-tetrachlorodibenzo-p-dioxin
MoL Pharmacol.
28, 357-363
13. Bradfield,
relationships
as
in rat liver.
Toxicol. Environ.
Health
21, 311-323
14. Wortelboer, H. M., de Kruif, C. A., Cassee, F R., Falke, H. E.,
Noordhoek, J., Blaauboer, B. J., and van lersel, A. A. J. (1990)
Modification
of xenobiotic metabolism by dietary indoles in rats
in vivo
and in vitro. In Drug Metabolizing Enzymes: Genetics, Regulatio,n and Toxicology
(Ingelman-Sundberg,
M., Gustafsson,
J. - A., and Orrenius, S.,eds), Abstr. 395, Karolinska Institutet,
Stockholm
P-450 (P-450j)
by fasting.
107 7-1083
18. Song, B.-J.,Gelboin, H. V., Park, S-S., Yang, C. S.,and Gonzalez, F. J. (1986) Complementary
DNA
and protein sequences
of ethanol-inducible rat and human
cytochrome P-450: tran-
METABOLISM
scriptional
zyme. j
and post-transcriptional
regulation
BioL Chem. 261, 16689-16697
of the
rat
en-
J.,
22. Tinel,
M., Belghiti,
J.,
Descatoire,
V., Amouyal,
N-nitrosomonooxy-
G., Letteron,
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
in mouse
lung
microsomes
and its inhibition
by isothiocyanates.
Cancer Rg.s. 0,
6817-6822
24. Guengerich,
F. P., and Kim, D. -H. (1991) In vitro inhibition
of
dihydropyridine oxidation and aflatoxinB1 activation in human
liver microsomes
by naringenin
and other
flavonoids.
Carcino-
33. Ma,
Q.,
Dannan,
G. A., Guengerich,
(1989) Similarities
and differences
in the regulation
of hepatic
cytochrome P-450 enzymes by diabetes and fastingin male rats.
Biochem. Pharmacol. 38, 3179-3184
34. Dong, Z., Hong, J., Ma,
Li, D., Bullock, J., Gonzalez, F J.,
Q.,
35. Wang,
rabbits.J. Biol.
Chem.
257:
chemicals
8472-8480
39. Perrot, N., Nalpas, B., Yang, C. S., and Beaune, P. (1989)
Modulation
of cytochrome
P450 isozymes in human liver, by
ethanol
and drug intake.
Eur. j C/in. Invest. 19, 549-555
40. Yang, C. S., Yoo, J. -S. H., Ishizaki, H., and Hong, J. -Y. (1990)
Cytochrome
P45011E1: roles in nitrosamine
metabolism
and
mechanisms
of regulation. Drug Metab. Rev. 22, 147-160
41. Guengerich,
F P., Kim, D. -H., and Iwasaki, M. (1991) Role of
human cytochrome
P-450 IIE1 in the oxidation of many low
molecular
weight
cancer
suspects.
of nitrosopyrrolidine
to a mutagen in
86, 1073
43. Ding, X., Koop, D. R., Crump, B. L., and Coon, M. J. (1986)
Immunochemical
identificationof cytochrome
P-450 isozyme
3a (P-4SOALc) in rabbit nasal and kidney microsomes and evidence for differential induction by alcohol. MoL PharmacoL 30,
rat esophagus.
Gastroenterology
370-378
44. Yoo,J.-S. H., Park, H-S., Ning, S. M., Lee, M.-J., and Yang,
C. S. (1990) Effects of thiamine
deficiency
on hepatic
cytochromes P450 and drug-metabolizing
enzyme activites. Biochem.
Pharmacol. 39, 519-525
45. Griciute,
L., Castegnaro,
M., and Bereziat,
J. -C. (1981)
Influence
of ethyl alcohol on carcinogenesis
with N-nitrosodimethylamine.
Cancer Let!. 13, 345-352
46. Anderson,
L. M. (1988) Increased numbers
of N-nitrosodimethylamine-initiated lung tumors in mice by chronic coadministration
of ethanol.
Carcinogenesis (London) 9, 1717-1719
47. Koop, D. R., and Casazza,J. P. (1985) Identificationof ethanol-
inducible P-450 isozyme 3a as the acetone and acetol monooxygenase of rabbit microsomes. j Biol. Chem. 260, 13607-13612
48. Ekstrom,
G., and Ingelman-Sundberg,
M.(1989)
Rat liver
microsomal
NADPH-supported
oxidase
activity and
lipid
peroxidation
dependent
on ethanol-inducible
cytochrome
P-450 (P-450IIE1).
Biochem. Pharmacol.
38, 1313-1319
49. Bailey, D. G., Edgar, B., Spence, J. D., Munoz, C., and Arnold,
J. M. 0. (1990) Felodipine and nifedipine interactions with
grapefruit juice. C/in. Pharmacol.
Ther. 47, 180
50. Guengerich,
F P. (1981) Oxidation
of toxic and carcinogenic
744
Vol. 6
January
1992
Toxicol.
by human
cytochrome
P-450
enzymes.
Res.
Chem.
4, 391-407
H. I., Dashwood,
(1978) 931-934
54. Michnovicz,
J. J., and
tradiol metabolism
by
j Nati. Cancer Inst. 82,
55. Morse, M. A., Amin,
S. G., Hecht,
F. -L.
nitrosamine
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
in
Galati,
A.
J.,
and Wagner,
S. A. (1991) Inhibitory
effects of
and
Gray,
K. (1988)
benzylamine-induced
occurring
thioether,
Chemoprevention
of N-nitrosomethyl-
esophageal
cancer in rats by the naturally
diallylsulfide.Cancer Res. 48, 6872-6875
58. You, W. -C., Blot, W. J, Chang, Y. -S., Ershow, A., Yang, Z. T.,
An, Q., Henderson,
B. E., Fraumeni,J.
F,Jr., and Wang, T-G.
(1989) Allium vegetables and reduced risk of stomach cancer.
j NatL Cancer Inst. 81, 162-164
59. Wattenberg,
L. W. (1978) Inhibition of chemical carcinogenesis.
j Nati. Cancer Inst. 60, 11-18
60. Imaida, K., Fukushima,
S., Shirai, T., Ohtani, M., Nakanishi,
K., and Ito, N. (1983) Promoting
activities of butylated
hydroxyanisole
and butylated hydroxytoluene
on 2-stage urinary
bladder
carcinogenesis
and
inhibition
of
y-glutamyl
transpeptidase-positive foci development
Carcinogenesis 4, 895-899
YANG ET AL.