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Dietary

effects

on cytochromes

P450,

xenobiotic

metabolism,

and toxicity
CHUNG

S. YANG,

JOHN

F. BRADY,2

AND

HONG

JUN-YAN

Laboratory

for Cancer Research, Department


of Chemical Biology
Rutgers University,
Piscataway, New Jersey 08855-0789,
USA

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,

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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

effect of diet on P450-dependent


monooxygenase
activiwas clearly
demonstrated
in the pioneering
work of
Wattenberg
(10), who discovered
that rats on commercial
rat
chow had 68-fold
higher
intestinal
benzo(a)pyrene
(BP)
hydroxylase
activity than those on a purified
diet. By adding
dry vegetable
powder to the purified
diet, Brussels
sprouts,
cabbage,
turnips,
and other vegetables
were found to be inducers
of intestinal
BP hydroxylase
in rats. The effects of
cruciferous
vegetables
and their components
on drug metabolism have since been studied
extensively.
Three
autolytic
products
of indolylmethyl
glucosinolate
(glucobrassicin):
indole-3-carbinol,
indole-3-acetonitrile,
and indole-3-carboxyaldehyde,
isolated
from Brussels
sprouts,
were found to induce intestinal
and hepatic
BP hydroxylase
in rats. The
structures
of some of the nonnutritive
dietary
compounds
are illustrated
in Fig. 2. Indole-3-carbinol
is the most potent
inducing
agent among
these indoles.
Its induction
of BP
hydroxylase
and ethoxyresorufin
dealkylase
activities
is believed to be mainly due to the induction
of P450 1A1 in the
intestine
and P450s IA1 and 1A2 in the liver (11).
It was demonstrated
that after an oral dose of indole-3carbinol
to rats, P450 lAl mRNA
was elevated
severalfold
ties

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

Figure 1. Possible sites for dietary effects on P450 enzymes. The


P450 2E1 gene is used in the illustration.
In addition to affecting
the rates of transcription
and translation,
dietary chemicals may
affect the rates of degradation
of P450 mRNA and protein. Dietary
chemicals
may serve as substrates.
They may also interact with
P450 enzymes and NADPH:P450
reductase, causing inactivation
of P450, or inhibition or enhancement
of the monooxygenase
activities.

in the liver and colon, and P450 1A2 mRNA


was also elevated in the liver (11). The induction
of P450 IAI involves the
binding
of the inducer
to the Ah receptor.
Nevertheless,
indole-3-carbinol
has only low binding
affinity
to the Ah
receptor,
whereas
indolo[3,2-b]carbazole
has a much higher
affinity (12). It is suggested
that under the acidic conditions
in the stomach,
indole-3-carbinol
can be converted
to
indolo[3,2-b]carbazole
or other
acid
reaction
products
(RXM)
(13) that bind to the Ah receptor
and thereby increase
the transcription
of the P450 1A1 gene. This suggestion
is
supported
by the observation
that the inductive
effect was
found when indole-3-carbinol
was given to rats orally but not
when
given
intraperitoneally
(13). Acid-treated
indole-3carbinol
was much more effective
than untreated
indole-3carbinol
in inducing
ethoxyresorufin
activity in primary
cultures of rat hepatocytes
(14). Certain
flavones
may also induce P450 IA1 by binding
to the Ah receptor
and subsequently
activating
the P450
1A1 gene.
A second example
of transcriptional
regulation
is the induction
of P450 2B1 by diallyl sulfide. Diallyl sulfide, a component
of garlic oil, has been shown to induce
rat hepatic
P450 2B1 based on the increase of immunodetectable
protein
and pentoxyresorufin
dealkylase
activity (15). Recent studies
in our laboratory
indicate
that this induction
is accompanied
by the elevation
of 2B1 mRNA
levels. Nuclear
run-on experiments indicate
that after administration
of diallyl sulfide, the
transcriptional
rate of the P450 2B1 gene was increased
markedly,
and was observable
at 4 h after treatment
(16). In
primary
culture
of rat hepatocytes,
P450 2Bl was not induced by diallyl sulfide but by its metabolite
diallyl sulfone
(unpublished
results).
Posttranscriptional
mechanisms
may also be involved
in
the induction
of P450s by dietary factors. In the induction
of
P450 2E1 by fasting,
elevation
of P450 2E1 mRNA
was observed (17) but transcriptional
activation
could not be convincingly
demonstrated
by nuclear
run-on experiments
(unpublished
results).
Stabilization
of the mRNA
may play a
role in this induction.
In the induction
of P450 2E1 by
ethanol
and acetone,
elevation
of the mRNA
was not observed (18, 19). Protein
stabilization
or increased
translation
efficiency
may be involved
in this induction.

738

Vol. 6

lanuarv

1992

Inactivation

of P450

enzymes

When diallyl sulfide was given orally to rats, microsomal


Nnitrosodimethylamine
(NDMA)
demethylase
(indicative
of
P450 2E1 activity) decreased
markedly
in several hours. This
was followed
by a lowering
of the immunodetectable
P450
2El protein
level in microsomes
(15). The inactivation
of
P450 2E1 was also demonstrated
in vitro when diallyl sulfone, an oxidative
metabolite
of diallyl sulfide, was incubated
with microsomes
in the presence
of an NADPH-generating
system (15). The inactivation
was time, concentration,
and
NADPH-dependent,
following
a typical
suicide
inhibition
pattern.
It is believed
that diallyl
sulfone
is converted
by
P450 2E1 to a reactive
intermediate
that modifies
the heme
moiety of P450 2E1 (20). Phenethyl
isothiocyanate,
occurring
as a glucusinolate
in a variety of cruciferous
vegetables,
also
inactivates
P450 2E1 by a suicide mechanism
(21). Psoralens,
which are found in edible plants such as figs, celery, parsley,
and parsnip,
were shown to decrease
7-ethoxycoumarin
and
BP hydroxylase
activities
when
added
to human
liver
microsomal
incubations
in the presence
of NADPH
(22). It
was suggested
that methoxsalen
(8-methoxypsoralen),
bergapten
(5-methoxypsoralen),
and psoralen
are suicide inhibitors of P450 enzymes;
P450 lAl or 1A2 may be involved.
Enhancement

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-

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Flavone

Quercebn

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2. Structures

Tange,otin

Nob,I.bn

Kaenpfeoi

of some dietary

or related

compounds.

YANC FT At

tween P450 and NADPH:P450


reductase
and facilitating
the
flow of electrons
to P450. Administration
of flavone to neonatal rats also increased
the rate of zoxazolamine
metabolism several-fold
(4).
Inhibition

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-

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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-

fasting before an exin the P450 2E1 level.

chrome

c reductase

microsomal
ethoxycoumarin
hydroxylase

sumption
ALCOHOL
CONSUMPTION
METABOLISM

gus

ON

postulated
(36).
been
demonstrated
enzyme
catalyzes

drug

of P450 2E1 has subsequently


and humans
(38,
39). This
of small
molecules
such as

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,

have been investigated


extensively
conflicting results in older literature

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.

On the other hand, during early stages of riboflavin


deficiency,
the levels of some P450s may be increased,
possibly
to compensate
for the decreased
NADPH:P450
reductase
levels;
some of the monooxygenase
activities
such as NDMA
demethylase,
aniline hydroxylase,
and aminopyrine
demethylase activities
were elevated.
When
the deficiency
was prolonged,
the level of P450 enzymes
decreased,
resulting
in
depressed
levels of all P450-dependent
activities
using substrateS such as BP, aminopyrine,
ethylmorphine,
N-methylaniline,
aniline,
and acetanilide.
Therefore,
mild deficiency
and severe deficiency
had opposite
effects on the metabolism
of certain
drugs and carcinogens
(8).

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

was also shown

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,

aniline, BP, 7-ethoxycoumarin

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

Folic acid deficiency


Aluminum
Cadmium,

cobalt,

heavy

metals-high

Calcium

deficiency

Magnesium

Induction

of codeine,

ethylmorphine,

aniline,
zoxazolamine,

acetanilide
BP

BP

of P450 2B1 by barbiturates

1 P450 and related

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,

1 P450 2E1, reductase,


cytochrome
I NDMA, acetaminophen,
aniline,

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

and signs used:


(2, 3, 5, 8, 9).

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-

DIETARY EFFECTS ON XENORIOTIC

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

of P450 2El can contribute


to oxidative
stress in vivo. The
application
of dietary-derived
P450 2E1 inhibitors
and suppressors
for the prevention
of acetaminophen
toxicity
is being explored
in our laboratory.
Of particular
importance
are
applications
with alcoholics
or patients
taking
isoniazid
whose P450 2El levels are known to be elevated.

DIETARY

EFFECTS

TOXICITY,

AND

ON

DRUG

METABOLISM,

CARCINOGENESIS

Food and dietary components


may affect the fate of a drug or
toxicant
by the following
mechanisms:
1) altering
the rates
of its absorption
and uptake,
2) reacting
or tightly binding
with the drug, 3) competing
with the drug for binding
to
plasma
proteins,
and 4) affecting
phase
I and phase
II
metabolism.
Interfering
with P450-dependent
metabolism
appears
to be the most selective mechanism
by which dietary
components
exert their effects on drug metabolism
and carcinogenesis.
For example,
the observation
that the drinking
of 200 ml of grapefruit
juice markedly
inhibited
the oxidation of nifedipine
and felodipine
in human
volunteers
(49)
may be interpreted
on the basis that grapefruit
is rich in
quercetin
and naringenin,
which are effective
inhibitors
of
P450 3A4, the isozyme
responsible
for the metabolism
of
these dihydropyridine
drugs (24). P450 3A4 is also important
in the activation
of aflatoxin
B, in humans
(50). It may be
speculated
that grapefruit
consumption
would inhibit
the
bioactivation
of aflatoxin
B, and could inhibit
hepatocarcinogenesis
in populations
exposed to rather high concentrations of this carcinogen.
Indoles and isothiocyanates
are two major classes of compounds
that occur as glucosinolates
in cruciferous
vegetables. The actions of indole-3-carbinol
and phenethyl
isothiocyanate
may account
for some of the reported
inhibitory
actions

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.

The FASEB lournal

YANC

FT Al

This work was supported by National Institutes of Health grants


ES03938, CA46535, and CA37037, a grant from the American Institute for Cancer Research, and NIEHS Center grant ES05022.
The authors wish to thank Ms. Dorothy Wong for her excellent
secretarial
pare

the

assistance

and

Ms.

Marie

Leithauser

for helping

to pre-

manuscript.

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