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Introduction
During pregnancy, the fetus may be exposed to
maternally-administered drugs and other xenobiotics. Significant
xenobiotic metabolism is now recognized as occurring in the
mammalian fetus, mostly by a range of biotransformation
phase I and phase II enzymes. The fetal liver appears to be
the most important organ for fetal drug
metabolism[1,2]. It is well known that cytochrome (CYP)P450 is a multigene
superfamily that plays a critical role in the bio-oxidation of
xenobiotics, such as drugs, pesticides, and carcinogens, as
well as endogenous agents, including fatty acids and
steroid hormones[3]. Of the 17 CYP families in humans, the first
3 families are largely involved in xenobiotic
metabolism[4]. The majority of CYP are found in the liver and some are found in
extrahepatic tissues, such as kidneys, lungs, small intestines,
brain, skin, and placenta. These extrahepatic CYP
are likely to participate in tissue-specific
biotransformations[5]. Although a great deal of information has been acquired relating to the
identification and the characteristics of different CYP isoforms
in adult organisms[6], the role of these enzymes in the
developing embryo and fetus has received relatively little attention.
Phase II drug-metabolizing enzymes are characterized by their
abilities to synthesize metabolites that are generally more
water soluble than the parent drug. In the adult, this
facilitates biliary and renal elimination. In the fetus, however, the
production of water-soluble metabolites may paradoxically
increase fetal exposure to the metabolite, as the water-soluble
compounds are less able to cross the placenta for disposal
by the mother. Substances excreted in fetal bile and urine
can accumulate in the amniotic fluid and be swallowed and
recirculated in the fetus[1,7]. Given the important role of
conjugation enzymes in drug and toxicant
disposition, the investigation of phase II enzyme (glutathione S-transferase [GST] and uridine diphosphoglucuronyl transferase [UGT])
activities is necessary to understand the risk of fetal xenobiotic
exposure.
The adrenal is an important endocrine organ that
synthesizes steroid hormones. Adrenal toxicity may have a
greater impact on growth, development, and sexual
maturation in fetuses than in adults[8]. As an important endocrine
organ in fetal development, the adrenal exhibits the most
striking differences in structure and function between fetal
life and adulthood. Many reports have focused on the
morphological and histological changes in the adrenal during
the fetal maturation process[9]. However, to the best of our
knowledge, about the evolution process of its enzymology,
function, and regulation are still unclear. It was found that
steroidogenesis of fetal adrenals could be affected by
several xenobiotics, such as
estrogen[10] and
nicotine[11], which are the substrates and inducers of phase I enzymes, but
through what mechanism do these xenobiotics affect
steroidogenesis? Our recent study investigated the
correlations among xenobiotics, xenobiotic-metabolizing enzymes,
and steroidogenesis in human fetal adrenal cortical cells
during fetal development with respect to possible
toxicological significance. The observations showed that
3-methylcholanthrene, phenobarbital, or dexamethasone could
interfere with the synthesis of cortisol, aldosterone, and
progesterone. This intervention is likely to take effect through
the activation of xenobiotic metabolizing-related CYP
isozymes[12]. Moreover, our research further demonstrated
that prenatal exposure during mid and last gestation to
nicotine and caffeine induced typical intrauterine growth
retardation (IUGR) in rodents accompanied with a depressed
fetal adrenal steroidogenesis
function[13]. Xenobiotic metabolizing-related enzymes may exist in fetal adrenals and
participate in the toxic mechanism of fetal development. In this
study, we examined the changes of activities of several
xenobiotic metabolizing-related phase I and phase II enzymes:
CYP1A1, CYP2A6, CYP2E1, CYP3A7, GST, and UGT in human fetal adrenals, and compared them with those in fetal
livers.
Materials and methods
Chemicals Coumarin, 7-hydroxycoumarin, testosterone,
aniline, p-aminophenol, 3-methylcholanthrene (3MC),
7-ethoxyresorufin, resorufin, 6β-hydroxytestosterone
(6β-OHT), isocitric acid, isocitric acid dehydrogenase,
collagenase I, DMSO, 1-chloro-2,4-dinitrobenzene (CDNB), cumene
hydroperoxide (CH), ethacrynic acid (EA),
bromosulfophthalein (BSP), reduced glutathione (GSH), glutathione
reductase, uridine diphosphate glucuronic acid (UDPGA),
p-hydroxy-biphenyl (HBP), 7-hydroxy-4-methylcoumarin
(HMC), and a reduced form of NADPH were obtained from
Sigma (St Louis, MO, USA). Fetal calf serum and modified
McCoy's 5A medium were purchased from Gibco (Carlsbad,
CA, USA). The One-step PCR kit was purchased from
TaKaRa Biotechnology (Dalian, China). Oligonucleotide
primers were customly synthesized by Sangon Biological
Engineering Technology (Shanghai, China). All other
chemicals and reagents were of analytical grade.
Biological samples and treatment Human fetal tissues,
ranging from 23 to 39 weeks of gestation, were obtained from
legal abortions and did not exhibit any morphological
evidence of defects. The fetal age was obtained from clinical
information and confirmed by fetal foot-length measurement.
The fetuses were collected within 2 h of abortion, and both
the adrenal and liver were obtained from the same fetus. The
samples of 2 adult livers and 2 adult adrenals, which acted as
positive controls, were taken by biopsies during laparotomy
in patients with liver or adrenal disease. Tissues were
immediately frozen at -80 oC and used within 3 months. The study
was approved by the Ethical and Research Committee of
Basic Medical School of Wuhan University (Wuhan, China),
and written informed consent was obtained from each adult,
pregnant woman. Clinical data of the specimens are shown
in Table 1.
Human fetal specimens were obtained from therapeutic
abortion and legal abortion at 23_39 weeks of gestation and
did not exhibit any morphological evidence of defects. Both
the adrenal and liver are acquired from the same fetus. The
samples of 2 adult livers and 2 adult adrenals, which acted as
positive controls, were taken by biopsies during laparotomy
in patients with liver or adrenal disease.
Subcellular fraction isolation The isolation procedure
of the subcellular fractions is described. In brief, the piece of
adrenal or liver tissue was homogenized (1:4,
w/v) in ice cold Tris-HCl buffer (50 mmol/L, pH 7.4) containing 0.1
mmol/L EDTA. Then the homogenate was spun at
9000×g for 20 min at 4 oC to remove nuclei and mitochondrial
pellets. The supernatant (S9) was spun at 105
000×g for 60 min at 4 oC to obtain the pellet (microsome) and supernatant
(cytosol). The microsomal pellet was suspended in sucrose
(0.25 mol/L) corresponding to 1 g of tissue per mL and stored
at _80 oC for further assays. The protein concentrations
were determined by the Lowry method[14] using bovine
serum albumin (BSA) as standard.
Enzyme assays Due to the lower enzyme activities that
existed in the fetal tissues, the enzymatic activities with
different incubational time, microsomal protein contents, and
substrate concentrations were measured in advance, so as
to establish an optimal reaction system.
7-Ethoxyresorufin O-demethylation (EROD) and coumarin
7-hydroxylation (COH) were assayed using the modified
fluorescent method[15,16]. In brief, the reaction mixture of EROD
included microsomal protein 1_2 mg, Tris·HCl 50 mmol/L (pH
7.8), MgCl2 2.5 mmol/L, KCl 50 mmol/L, BSA 12 g/L, 7-ethoxyresorufin 2 µmol/L, and a NADPH-generating
system, including NADP+ 0.4 mmol/L, isocitric acid 10
mmol/L, and isocitric acid dehydrogenase 0.6 units. The
reaction was initiated with the NADPH-generating system
and stopped by the addition of ice-cold methanol (2.5 mL)
at 30 min. The COH reaction mixture included sodium
phosphate buffer (pH 7.4) 50 mmol/L, KCl 50 mmol/L,
MgCl2 2.5 mmol/L, BSA 1 g/L, coumarin 5 mmol/L,
microsomal protein 4 mg, and the NADPH-generating system.
The reaction was initiated by the addition of the
NADPH-generating system and stopped by 20%
(v/v) trichloroacetic acid (0.125 mL) at 120 min.
Aniline hydroxylation was studied by measuring the
formation of p-aminophenol[17]. The hydroxylation was carried
out under similar conditions with 8 mmol/L aniline. After 120
min incubation at 37 oC, the reaction was terminated by 0.2
mL of 50% (v/v) trichloroacetic acid.
Testosterone 6β-hydroxylation was assayed using the
HPLC method[18]. The incubation mixture was incubated for
60 min at 37 oC in a 200 µL volume containing potassium
phosphate buffer (pH 7.4) 80 mmol/L,
MgCl2 5 mmol/L, testosterone 250 µmol/L, and microsomal protein 0.3 mg. The HPLC
system was composed of a pump (LC-10AT, SHIMADZU, Kyoto, Japan) and a UV detector (SPD-10A, SHIMADZU,
Kyoto, Japan). The HPLC column (length×diameter:
250×4.6 mm; 5 µm particle size; Dalian, China) was used with a
C18 Guard-pack precolumn (10 μm particle size, 20×4.6 mm;
SHIMADZU, Kyoto, Japan). A flow rate of 1.0 mL/min was
used and the UV detector was set at 245 nm. All
chromatography was performed at room temperature. The overall run
time for the chromatographic separation was 30 min. The
retention time of 6β-OHT was 7.41±0.10 min.
The UGT activities were measured using the fluorescence
method with HBP and HMC as
substrates[19]. The reaction mixture (0.5 mL) included Tris-HCl buffer (pH 7.4) 0.5 mol/L, MgCl2 5 mmol/L, 0.01%
(v/v) Triton X-100, HBP (or HMC) 0.5 mmol/L, microsomal protein 2 mg,
and UDPGA 0.6 mmol/L. The reaction was initiated by the addition of
UDPGA and stopped by 10% (v/v) perchloric acid (0.5 mL)
and chloroform (2 mL) at 60 min.
GSH conjugations with CDNB, CH, EA and BSP as the
substrates were measured for determining the activities of
total GST, αGST, πGST, and μGST using the
spectrophotometric method[19_21].
Preparation of tissue total RNA and RT_PCR
Total RNA was isolated from the frozen tissues according to the
instructions of the Trizol reagent. The concentration and
purity of RNA were determined using a spectrophotometer
(UV-1601, Shimadzu, Japan). Total RNA was stored in diethyl
pyrocarbonate (DEPC)_H2O at _80
oC until used.
RT_PCR was performed in an attempt to detect expressed
CYP1A1 mRNA corresponding to negative enzyme assay
results. There was 1 negative control without the template
RNA and 2 positive controls performed with adult samples
in every series. The primer was designed according to
Hakkola et al[22]. The PCR cycling conditions were as follows:
94 oC for 45 s, 55 oC for 45 s, and 72
oC for 50 s for 35 cycles. An aliquot (4 µL) of the RT_PCR production was separated
on a 1.5% (w/v) agarose gel and visualized by ethidium
bromide with a UV light.
Data analysis Data are presented as mean±standard
deviation. We paired the enzyme activities of the adrenal
and liver from the same fetus. Statistical Packages for Social
Sciences was used for the data analysis (SPSS, Chicago, IL,
USA). The difference between the adrenals and livers was
analyzed using the unpaired t-test. The correlation was
examined by linear regression analysis. The level of
significance was set at P<0.05.
Results
Phase I enzymes
CYP1A1 enzyme activity and mRNA expression EROD is well known as a marker for CYP1A1 enzyme
activity[15]. No detectable EROD activity was measured in
either adrenal microsomes (Table 2) or the 3MC-treated
adrenal cortical cells in
vitro[12] in our work.
Due to the negative result on CYP1A1 activity, the
expression of CYP1A1 mRNA in the adrenals and livers were also
investigated using the RT_PCR method and taking 2 adult
livers and 2 adult adrenals as positive controls. The
representative amplification results by the CYP1A1 primer are shown
in Figure 1. The positive expression occurred in 73% of fetal
adrenals and 78% of fetal livers. No remarkable gestational
time and fetal sex-related differences were observed.
CYP2A6 activity Coumarin was chosen as a selective
substrate for the determination of human CYP2A6
activity[16]. The results showed that CYP2A6 enzyme activity occurred
in all of the fetal adrenal and liver microsomes, and the
average level in adrenals was 457±10
nmol·min_1·g_1, which was
82% of that in the fetal livers (P<0.05; Table 2). The activity
in the adrenal showed a gestational time-dependent increase
(r=0.694, n=10, P<0.05; Figure 2). Meanwhile, the activities
in the fetal liver showed a sex-related difference, and the
level of the males (684±198
nmol·min_1·g_1) was higher than
that of the females (503±40, P<0.05; Figure 3).
CYP2E1 activity Aniline hydroxylase is a CYP2E1
enzyme marker[17]. Our study found that the activity in the fetal
adrenals was 96±41
nmol·min-1·g-1, which was 92% of that in
fetal livers (Table 2). There were no significant fetal sex and
gestational time-dependent differences of the activity
between the adrenals and livers.
CYP3A7 activity Testosterone is always chosen as a
selective substrate of CYP3A7 in human fetal
experiments[23]. Our results showed that the level of testosterone
6β-hydroxylation in fetal adrenals was 14±3
nmol·min-1·g-1, which
was 33% of that in fetal livers (P<0.01; Table 2). No
remarkable gestational time and fetal sex-related differences were
observed.
Phase II enzymes
UGT activities UGT activities using HBP and HMC as
substrates could be detected in all fetal adrenals and were
9% and 3%, respectively, of those in the fetal livers (Table 3).
No gestational time- and sex-related differences were
observed in the fetal adrenals. In the fetal livers, there were 6
and 21-fold interindividual variations for HBP- and
HMC-UGT activities, respectively, which contributed to the
development of UGT enzymes with increasing gestational time
(HBP-UGT: r=0.744, n=10, P<0.01; HMC-UGT:
r=0.840, n=10, P<0.01; Figure 4).
GST isoforms activity In the fetal adrenals, GST isoforms
were found to primarily distribute in the cytosols. The
activities of the cytosolic total GST, αGST, πGST, and
μGST in the fetal adrenals were 0.4, 0.5, 4.4, and 8.3-fold, respectively,
of those in the fetal livers (P<0.01; Table 4). There were
negative correlations between the gestational time and
pGST activity in both the fetal tissues (adrenals:
r=-0.579, n=10, P<0.05; liver:
r=-0.632, n=10, P<0.05; Figure 5).
Discussion
Exposure during gestation to many xenobiotics, such as
drugs and environmental chemicals, is believed to induce
IUGR, bring about morphological defects, or
cause in utero death of the embryo or fetus in the surviving
offspring[24,25]. The adrenal is very important for the synthesis of steroid
hormones and any interference in adrenal development by
xenobiotics could have a profound effect on homeostasis. It
was reported that the weight of fetal adrenal during mid
gestation was 10%_15% of the fetal liver weight, and in
newborns, was 20-fold higher than that in adults, although
there was a 100-fold difference in adult organ weights
between the livers and adrenals[26]. The biotransformation
enzymes may be of some importance, particularly when they
perform functions in protecting this organ from
xenobiotic-induced toxicity. In view of these facts, we investigated the
activities of several important xenobiotic activating-related
phase I and phase II enzymes in human fetal adrenals.
CYP1A1, which exists primarily in extrahepatic tissues, is
implicated in the activation of some xenobiotics with
possible deleterious effects. 3MC and other environment
carcinogens are substrates and selective inducers of
CYP1A1[27]. There was some evidence of CYP1A1 expression in the
human fetal liver[22,28], but the expression of this enzyme in fetal
adrenals has not been reported until now. In our study, no
detectable CYP1A1 activity was measured
spectrophotometrically in either fetal adrenal microsomes or 3MC-induced fetal
adrenal cells[12], but the expression of the CYP1A1 mRNA in
the majority of fetal adrenals and livers were observed using
RT_PCR technique. Our recent study also demonstrated the
existences of CYP1A1 mRNA as well as arylhydrocarbon
receptor mRNA in rodent fetal adrenals during mid and last
gestation[13]. These results showed the existence of the
CYP1A1 isoform in fetal adrenals, but the activity was lower
than the minimal detectable level of the enzyme assay.
Members of the human CYP2A subfamily are known to
metabolize several promutagens, procarcinogens, and
hepatotoxins. Gu et al[29] found that the CYP2A6 protein can
express in extrahepatic tissues, and the level in olfactory
mucosa was much higher than that in the liver of the same
fetus. In our study, the metabolic activity of CYP2A6
occurred in all of the human fetal adrenals and was
comparative to that of the liver. Meanwhile, the activity showed a
good gestational time-dependent manner. The results
suggested that the adrenal of the human fetus may be a target
tissue for the toxicity of chemicals that are activated by
CYP2A6.
The catalysis of most substrates by CYP2E1 results in
the formation of toxic intermediates, making it one of the
most toxicologically-significant CYP isozymes. Roberts
et al[30] demonstrated that CYP2E1 is present at relatively high
concentrations in the endoplasmic reticulum of the human
liver and in lower concentrations in various other
extrahepatic tissues. However, CYP2E1 has not been documented
in human adrenals. In our study, aniline hydroxylase (a marker
for the CYP2E1 isozyme) could be detected in fetal adrenals
and was comparative to that of the liver, which suggests
that the fetal adrenal may be easily attacked by xenobiotics
during development.
Among the members of the CYP3A subfamily, CYP3A7
is the major CYP isoform detected in the human embryonic,
fetal, and newborn liver. It plays an important role in the
biotransformation of endogenous compounds and is capable
of metabolizing potential environmental pollutants (eg
aflatoxin B1)[31]. Although CYP3A7 is considered human fetal
liver form, our observations showed that it was also
expressed in fetal adrenals, and the levels of activity in fetal
adrenals was 33% of that in the fetal livers.
In the adult liver, UGT is one of the most predominant
biotransformation phase II enzymes. There was some
evidence of UGT expression in the fetal liver[32]
and extrahepatic tissues, such as the
kidney[33]. Chauhan et
al[34] found that UGT activity developed during the late fetal period and
reached almost 60% of the adult activity at term in the mouse
fetal liver; the activity was transplacentally inducible by
β-naphthoflavone and 3-methylcholanthrene. In our study,
tissue-specific differences for HBP- and HMC-UGT were
observed in fetal adrenals and livers, and the activities in
adrenals were much lower. This result indicated that UGT
was also primarily distributed in the liver during the fetal
period.
The family of GST enzymes catalyzes the conjugation of
glutathione with a wide variety of nucleophiles and plays an
important role in protecting cells from oxidative injury. In
humans, there are 4 main classes of GST: α, π, μ, and
θ[35]. Immunohistochemical determination in the human embryo at
8 weeks' gestational age showed that αGST and πGST were
present in hepatocytes, gastrointestinal epithelium, adrenal
gland medulla, and tela chorioidea in the
telencephalon[21]. Furthermore,
Mera et al[36] proved immunohistochemically
that πGST was the main form of the GST family in the fetal
liver, but aGST was the main form in the adult liver. In our
study, CH, EA, and BSP were chosen as the selective
substrates of the αGST, πGST, and μGST isozymes, respectively.
The results showed the existence of αGST, πGST, and μGST
activities in human fetal adrenals. The activities of
pGST and mGST in fetal adrenals were found to be much higher
than those in fetal livers. We also demonstrated that
πGST once was the main isozyme by a correlation analysis
between gestational time and fetal adrenal πGST activity. The
cause of the higher activities of GST isozymes in fetal adrenals
might considerably contribute to the local active
biotransformation during development.
In summary, our results showed that the human fetal
adrenal possessed perfect xenobiotic-metabolizing enzymes,
which includes not only phase I enzymes (CYP1A1, CYP2A6,
CYP2E1, and CYP3A7 families), but also phase II enzymes
(UGT and GST families). The metabolizing capacities of CYP
and GST families in fetal adrenals as a whole were close to
those in fetal livers. The relatively high activities of
xeno-biotic-metabolizing enzymes might participate in the local
biotransformation of adrenal. These results suggested that
the adrenal could be an important xenobiotic-metabolizing
organ in fetal development and may play a potential role in
xenobiotic-induced fetal development toxicity.
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