|
|
Full-length article Acta Pharmacologica Sinica 2005 November; 26 (11): 1387-1394 Alterations of placental cytochrome P450 1A1 and P-glycoprotein in tobacco-induced intrauterine growth retardation in rats1 You-e YAN2, Hui WANG2,3, Ying-hong FENG2 2Department of Pharmacology, Medical College of Wuhan University, Wuhan 430071, China
1 Project supported by the Youth Foundation, Family Planning Commission of Hubei, China (No 30114).
Aim: To investigate the alterations of placental P-glycoprotein (P-gp) and cytochrome P450 1A1
(CYP1A1) at different gestational days (GD), and to explore the possible significance of placental P-gp and
CYP1A1 in tobacco smoke-induced intrauterine growth retardation (IUGR) in rats.
Methods: An IUGR model was produced by passive tobacco smoking from
GD 7 to parturition (GD 21) and predicted using fetal development parameters. Placental structure and function were
monitored by observing pathological alteration and antioxidative function, including the content of malondialdehyde and the
activities of superoxide dismutase and catalase (CAT). The expressions of
CYP1A1 and P-gp (mdr 1a and
mdr 1b) were detected using a reverse transcription polymerase chain reaction and immunohistochemistry.
Results: Placental pathological changes occurred and the malondialdehyde content increased, whereas the activities of superoxide dismutase and CAT
lowered, when compared to their controls. In the rat placenta of the tobacco group, the level of
CYP1A1 mRNA increased significantly; the level of
mdr1a mRNA increased significantly at GD 21 but not at GD 14, whereas the level of
mdr1b mRNA in different term remained stable; the expression of P-gp increased significantly only in full-term placenta.
Conclusion: The expression of placental
CYP1A1 and P-gp increased in tobacco-induced IUGR. Overexpression of placental
CYP1A1 can attribute to the metabolism of tobacco and the generation of reactive metabolites, which can trigger IUGR. As a compulsory
mechanism, upregulation of P-gp might decrease tobacco exposure to a developing fetus with IUGR. Key words intrauterine growth retardation; tobacco; placenta; cytochrome P450 1A1; P-glycoprotein; rats Note: Please read the complete
full text with Figures and Tables at
Introduction
There is ample epidemiological evidence that individuals
with intrauterine growth retardation (IUGR) carry an increased
risk of prenatal morbidity and mortality[1]
and that those born with IUGR are at a much greater risk of a wide range of
medical problems, such as mental handicaps and neurobehavioral
disorders[2,3]. There are various possible causes of
pathologically induced IUGR, and it is reported that some
xenobiotic exposure during pregnancy, including to tobacco
and drugs, could be attributable to
IUGR[4,5]. Clinically, there is no generally accepted effective treatment at present and,
therefore, the understanding of the mechanisms for
controlling fetal growth and the causes for IUGR induced by
xenobiotics is extremely important in the development of
therapeutic options.
The placenta is the organ responsible for the transfer of
nutrients and waste products between the fetal and maternal
circulations, and plays a pivotal role in fetal
growth[6]. The placenta receives oxygen from the maternal circulation and
is positioned in an oxygen gradient between the mother and
fetus. The placenta provides a link between the circulations
of 2 distinct individuals, but also acts as a barrier to protect
the fetus from xenobiotics in the maternal blood. Animal
studies, such as embryo transplant and cross breeding
experiments, have shown that, unlike postnatal growth, the
growth of the fetus is controlled predominately by the
uterine environment, and not by fetal or maternal genetic
factors[7]. Therefore, placental dysfunction can have an important
effect on fetal intrauterine development and can lead to fetal
diseases such as IUGR.
The placenta can perform xenobiotic transportation and
biotransformation. The transfer of foreign chemicals across
the placenta can be modified by metabolism in the placenta
itself. The extent to which drugs cross the placenta is also
modulated by the actions of placental phase I and II
drug-metabolizing enzymes. Cytochrome P450 enzymes in
particular have been well characterized in the placenta at the
level of mRNA, protein, and enzyme
activity[8]. In some cases, however, the enzymes can activate exogenous compounds,
making them toxic to the fetus[6]. Cytochrome P450 1A1
(CYP1A1) exists mainly in extra-hepatic tissue, and can
activate some xenobiotics with possible deleterious effects. The
alteration in CYP1A1 expression, for example, as a result of
inducers/inhibitors or maternal diseases, could potentially
adversely affect placental function and pregnancy
outcome[9]. Studies show that
CYP1A1 expresses in the placentas of women who are exposed to
cigarettes[6]. However, little is known about the possible changes of placental
CYP1A1 expression over the course of pregnancy and its roles in IUGR
formation.
Some drugs are pumped across the placenta by various
active transporters located on both the fetal and maternal
side of the trophoblast layer, and instances of drug-induced
birth defects have been in part blamed on the placenta¡¯s
apparent `leakiness¡¯ to maternal blood-borne
agents[8]. The impact of active transporters such as P-glycoprotein (P-gp)
on the disposition of drugs has been demonstrated in some
studies[10-12]. P-gp, which is encoded by the
mdr gene, is a membrane transport protein that functions as an efflux pump
for various cytotoxic compounds and, therefore, reduces the
intracellular concentrations of these
compounds[10]. Studies suggest that P-gp of the trophoblast cells is involved in
the function of the blood-placental barrier and is necessary
in reducing fetal drug exposure[11,12], although little is known
about the expression of placental P-gp in different
gestational time and its significance to IUGR.
It is difficult to correlate toxic chemicals and their
transportation and metabolism in the human placenta with IUGR.
The rat placenta is morphologically and histologically
similar to the human one; both of them are of the same
hemochorial type. Therefore, a rat model of IUGR
established by tobacco smoking is useful in providing us with
information about the relationships among xenobiotics,
placental transportations/metabolisms, and IUGR. To
understand the toxic mechanism of tobacco in IUGR formation, in
the present study, the alterations of placental
CYP1A1 and P-gp expressions were investigated in IUGR rats, so as to
explore the possible significance of placental
CYP1A1 and P-gp in tobacco-induced IUGR.
Materials and methods
Chemicals Thiobarbituric acid (TBA) and 5, 5¡¯-dithio-2,
2¡¯-dinitrobenzoic acid were obtained from Sigma. Trizol
reagent was obtained from Molecular Research Center and
One Step RNA PCR Kit was obtained from TaKaRa Biotechnology. Oligonucleotide primers were custom
synthesized by Sangon Biological Engineering Technology.
Rabbit anti-rat mdr1 and streptavidin-peroxidase (SP) reagent
were obtained from BOSTER Biotechnology. All other
chemicals and reagents were of analytical grade.
Animals Specific pathogen free(SPF) Wistar rats with
the weights of 190±18 g (female)/280±23 g (male) were
obtained from the Experimental Center of Medical Scientific
Academy of Hubei (China, No 2003-0005). Virgin female and
male rats were left undisturbed for 5 d and then subjected to
experimental conditions. Overnight, every 2 females was
mated up with 1 male rat and the occurrence date of a vaginal
plug was considered as gestational d 0 (GD 0). Pregnant
rats were then housed 1 per cage in an environment of
constant temperature (21±2 °C) and relative humidity (50%±10%)
with a 12 h L:D cycle. Ad libitum access to a standard diet
and water was permitted. The study protocol was in
accordance with the guidelines for animal research and was
approved by the Ethical and Research Committee of Wuhan
University.
Tobacco smoke exposure On GD 7, pregnant rats were
allocated to either a control group or a tobacco group. A rat
IUGR model was processed, with modification, according to
the procedure of Younoszai and
Li[13,14]. From GD 7 till parturition (GD 21), at 8:00, 11:00, 14:00, and 17:00, four pregnant
rats from the tobacco group were subjected to cigarette smoke
in a chamber measuring 40 cm×28 cm×18.5 cm for 15 min,
with the gross smoke concentration set at
9 g·m-3. The tar and nicotine yields of commercial cigarettes were 15 and
1.1 mg per cigarette, respectively. The control group was
sham-treated; that is, a group of 4 pregnant rats were in the
same chamber without cigarette smoke for 15 min. The
pregnant rats were weighed at GD 0, GD 7, GD 14, and GD 21.
Animals were killed at 8:00 on GD 14 and GD 21,
corresponding to mid and late gestational
time[15]. Each feto-placental unit was removed quickly from the uterus and placenta
specimens were excised, rinsed with cold saline, immediately
frozen in liquid nitrogen and stored at -80°C until used.
Placenta weight and fetal development parameters (fetal body
and organ weights, and fetal body and tail lengths) were
recorded.
Placental pathomorphological observations and
immunohistochemistry Fresh placentas were put into 4%
paraformaldehyde in phosphate buffered saline (PBS) for
24 h. The fixed placental samples were processed using
standard histological techniques and stained with hematoxylin
and eosin. The slides were observed using light microscopy
(Axiopstar PLUS).
Routine immunohistochemistry SP method was carried
out. The paraffin slides were deparaffinized with xylene and
rehydrated in a graded series of ethanol. To quench
endogenous peroxidase activity 0.3%
H2O2 was added for 10 min, and preimmune goat serum was used to block non-specific
binding sites. Sections were then incubated at 37 °C for
20 min with a rabbit polyclonal anti-mdr1 antibody diluted in
PBS (1:100). The slides were then incubated at 37°C for 15
min with an anti-rabbit secondary antibody and visualized
with a DAB chromatogen system. PBS substituted for
anti-mdr1 antibody for negative staining control. The slides were
observed under light microscopy (Axiopstar PLUS) and the
average gray level was measured using Photo Imaging
System (HMIAS-2000). The quantitative stereology was
performed in triplicates with 5 fields in each slide.
Tissue biochemical analysis Placentas at GD 21 were
homogenized with saline to be 10%
(w/v) homogenates. After the homogenates were centrifuged at 200×
g for 10 min, the supernatants were centrifuged at 9
000×g for 20 min and, finally, collected and stored at -30 °C for the further assays.
Placental protein concentrations were determined using the
Lowry method[16], with the bovine serum albumin (BSA) as
standard. The extent of lipid peroxidation was detected by
measuring malondialdehyde (MDA) content using TBA
according to a modified procedure described by Ondrejickova
et al[17]. The activities of superoxide dismutase (SOD) and
catalase (CAT) were measured as described
above[18, 19].
Preparation of placental total RNA Total RNA was
isolated from the frozen placentas according Trizol reagent
instructions. The protocol involved disruption of cells,
denaturation of nucleoprotein complexes, inactivation of
endogenous ribonuclease (RNase) activity and, finally,
removal of proteins and degradation of residual DNA by
nuclease digestion. The concentration and purity of RNA
were determined using a spectrophotometer (UV-1601,
Shimadzu) and adjusted to 1 µg/µL. Total RNA was stored
in DEPC-H2O at -80 °C until used.
Semiquantitative reverse transcriptase-polymerase
chain reaction The cDNA synthesis and polymerase chain
reaction (PCR) amplification were produced in 1 step using
Promega¡¯s reverse transcriptase-polymerase chain reaction
(RT-PCR) System. Different primers and PCR products are
shown in Table 1. The final concentrations of reagents in
the RT-PCR reaction system were as follows: 1×One Step
RNA PCR buffer, 5 mmol/L MgCl2, 1 mmol/L of each dNTP,
0.8 U/µL RNase inhibitor, 0.1 U/µL avian myeloblastosis
virus (AMV) RTase XL, 0.1 U/µL AMV-optimized
Taq,
0.4 µmol/L of each primer, and 0.02 U/µL placenta RNA in
each 50 µL reaction volume. For quantitative analysis of
mRNA expression, the housekeeping gene cyclophilin, an
internal loading control[22], was used to amplify together with
the specific target gene in 1 tube. RT-PCR reactions were
carried out in a thermal cycler: 50 °C for 30 min for reverse
transcription, then 94 °C, 2 min for RT inactivation; finally
72 °C, 5 min for a terminal elongation step following the
amplification cycles. PCR cycling conditions were as follows:
94 °C, 30 s; 62 °C, 45 s; 72 °C, 30 s, 45 cycles for
CYP1A1. 94 °C, 30 s; 54 °C, 60 s; 72 °C, 30 s, 30 cycles for
mdr1a. 94 °C, 30 s; 56 °C, 20 s; 72 °C, 30 s, 25 cycles for
mdr1b. DEPC-H2O substituted for placental RNA
for negative control. An aliquot (4 µL) of the RT-PCR reactions was separated on a 1.5%
agarose gel containing ethidium bromide, visualized under
UV light, photographed, and analyzed by densitometry
using Photo Documentation and Imaging System (Bio-1D). The
expression level of target gene mRNA was shown as the
ratio of the intensities of the target-specific band and the
CYC band individually.
Statistical analysis The experimental results were
expressed as mean±SD. Statistical Packages for Social
Sciences (SPSS) was used for data analysis. Analysis of
variance (ANOVA) was used for comparison of means of several
groups and c-square analysis was performed to test for
differences in proportions of categorical variables between 2
groups. The level of significance was set at
P< 0.05.
Results
Maternal body weights The change in pregnant rat body
weight is a useful, indirect indicator of physical development.
During the period of GD 7 to GD 21, there was a significant
decline in the body weight and percentage weight gain after
tobacco exposure (Figure 1).
Neonatal body weights and physical development
indexes Body weight was an important index for diagnosing IUGR
(IUGR was diagnosed by the standard that the mean body
weight in the treated group was less 2 standard deviations
than that in the control group)[23]. The offspring
in the tobacco group showed a lower average body weight (3.20 g)
than the control group (4.30 g) at GD 21, indicating fetal IUGR.
The ratio of IUGR increased to 44.74% (34/76) in the tobacco
group, whereas it was only 5.06% (4/79) in the control group.
In addition, the body and tail lengths, and liver and brain
weights of the tobacco group significantly lagged behind
those of control group at GD 21, with a suppression of
14.2 %, 8.9 %, 22.9 %, and 10.5 %, respectively
(P<0.01)
(Table 2).
Placental pathomorphology The rat placenta is
composed of 3 distinct zones: labyrinth, basal, and maternal
deciduas; where the labyrinth zone represents the main area
of maternal-fetal exchange. According to our results,
compared to those in the control group (Figure 2A), the obvious
changes occurred in the labyrinth and basal deciduas of the
full-term placenta in IUGR rats, such as through interstitial
and endovascular hemorrhage in the labyrinth zone, and
trophoblast cells necrosis in the basal zone (Figure 2B).
Full-term placental weight (0.39±0.08 g) of tobacco-induced IUGR
rats decreased by more than that of the normal placentas
(0.49±0.06 g).
Placental antioxidative system In the tobacco exposure
group, placental MDA content was significantly increased
by 50.0% (P<0.05), and the activities of SOD and CAT were
notably decreased by 58.2% and 30.6% (P<0.05,
P<0.01), respectively (Table 3).
Placental CYP1A1 mRNA expression No PCR product
for CYP1A1 mRNA was detected in normal placentas.
However, expression was detected in the placentas of the
tobacco exposure group; furthermore, the level at GD 21 was
approximately 1.39-fold higher than that at GD 14, with a faint
band (Figure 3).
Placental P-gp and mdr1 mRNA
expression Immunohistochemical analysis with anti-mdr specific antibody
showed strong positive staining in placenta trophoblasts
(Figure 4A-D). The P-gp level at GD 14 in the tobacco group
(Figure 4B) was similar to that of the normal placenta
(Figure 4A). However, the level at GD 21 in the tobacco
group (Figure 4D) was higher than that of normal placenta
(Figure 4C), almost 1.24-fold higher
(P<0.05).
The levels of mdr1a mRNA at GD 14 and GD 21 in the
placentas of tobacco groups were approximately 1.10-fold
and 1.32-fold higher than those in the normal placentas
(Figure 5). mdr1b mRNA level, however, was not
significantly different between the 2 groups (Figure 6).
Discussion
The placenta, which is derived from both fetal and
maternal tissues, is considered the first fetal organ to be exposed
to exogenous substances and plays an important role in
fetal intrauterine development. In the present study,
gestational tobacco smoking resulted in significantly delayed
fetal growth, as indicated by the fetal development parameters,
especially fetal body weight. Meanwhile, placental weight
decreased and obvious pathomorphological changes were
observed. Our result showed that the content of MDA was
higher and the activities of SOD and CAT were lower in IUGR
placentas, suggesting a decreased ability of placental
antioxidative defense. Therefore, these results
suggest that prenatal tobacco exposure has a specific and deleterious
effect on the placenta that secondarily limits fetal growth.
The placenta is now viewed as a metabolic barrier rather
than a physical barrier[24]. The placenta can perform
biotransformation that occurs in the liver. Numerous foreign
compounds reach the placenta through the maternal circulation
and placental tissue is capable of oxidizing several of them.
In present study, the expression of CYP1A1 mRNA was
detected in the placentas of the tobacco group, but not in the
normal placentas; furthermore, the expression of
CYP1A1 mRNA was higher in full-term placentas than that in
mid-term placentas. These results demonstrate that an increase
of CYP1A1 with environmental tobacco exposure is obvious
and that a time-response relationship exists during tobacco
consumption. There are many well-known
CYP1A1 inducers in tobacco, and smoking is one important source of
exposure to them. Increased CYP1A1 level might explain the
toxic mechanism because polyarylhydrocarbons can be
bioactivated by CYP1A1 and can generate reactive
metabolites[25]. Wu et al found that placental and fetal tissues were
capable of metabolizing benzo(a)pyrene [B(a)P], albeit to a
lower extent, and that CYP1A1 was involved in metabolism
of inhaled B(a)P[26]. In addition,
CYP1A1 can result in free radical formation and lipid peroxidation, and then affect
uterine redox environment and fetal growth. Oxidative stress
has been increasingly postulated as a major contributor to
dysfunction in IUGR[27], and our data indicates a decreased
ability of placental antioxidative defense. The present
finding of significant upregulation of placental
CYP1A1 mRNA subsequent to prenatal tobacco exposure supports a
hypothesis that an elevated placental
CYP1A1 level can be a trigger for IUGR.
In P-gp, generally, mdr1a appeared to be the
pharmacologically most relevant isotype. Schinkel
et al also indicated that mdr1a was the critical placental P-gp in
mice[28]. In a study by Lin,
Mdr1b was highly induced in the secretary epithelium endometrium of the uterus in mice during
pregnancy and might protect steroid secreting cells from
potentially damage[29]. In the present study, we analyzed P-gp
expression in the rat placenta during its maturation, using
the methods of immunohistochemistry. Intensive
immunoreactivity for P-gp was found in the developing labyrinth zone
of normal placentas. Furthermore, tobacco smoking induced
P-gp expression of the trophoblast cells only in full-term
placentas. We examined the changes of mdr1 levels in
different stages, using the RT-PCR method. We found different
P-gp members displayed distinct inductive patterns. Our
PCR data indicates that the expression of
mdr1a gene tends to increase from GD 14 to GD 21 in the normal placenta, which
correlates well with the results of Novotna
et al[30]. During tobacco smoke exposure, a significant increase in the amount
of mdr1a mRNA has been observed at GD 21, although it
remained steady at GD 14. The level of
mdr1b almost
remained steady at GD 14 and GD 21 between control and
tobacco groups. These results suggest that tobacco smoke
induced P-gp, especially mdr1a. The different expressional
patterns of mdr1a and mdr1b genes show that they were not
co-regulated during pregnancy and signified that the
expression of both genes probably underlied different regulation
pathways, which is supported by the recent data of
Lee[31,32]. P-gp was able to extrude a wide variety of structurally and
chemically unrelated compounds out of
cells[33]. Researches
have selected B(a)P as a potential P-gp
substrate[34]. There-fore, we suspect that the higher expression of P-gp in rat
IUGR placenta might be caused by the pumping out of part
of the tobacco toxins, to decrease toxicity and, thus, to
protect the fetus from potentially harmful xenobiotics during
tobacco exposure, which might be a compulsory mechanism
of IUGR. However, we cannot exclude the possibility that
there exist some P-gp inducers in tobacco.
Further experiments are needed to examine this possibility.
In summary, the present study has discussed the
abnormal alterations of placental morphology and function in
tobacco-induced IUGR. The expression of placental
CYP1A1 and P-gp increased in tobacco-induced IUGR.
Overexpres-sion of placental CYP1A1 can contribute to the metabolism
of tobacco and can generate reactive metabolites, which can
be a trigger for IUGR. However, upregulation of P-gp might
pump out part of the tobacco toxins, as a compulsory
mechanism of IUGR, to decrease tobacco exposure to the
developing fetus.
References
1 Genbacev O, McMaster MT, Zdravkovic T, Fisher SJ.
Disruption of oxygen-regulated responses underlies pathological changes
in the placentas of women who smoke or who are passively
exposed to smoke during pregnancy. Reprod Toxicol 2003; 17:
509-18.
2 Amin H, Singhal N, Sauve RS. Impact of intrauterine growth
restriction on neurodevelopmental and growth outcomes in very
low birth weight infants. Acta Paediatr 1997; 86: 306-14.
3 Spinillo A, Stronati M, Ometto A, Fazzi E, Lanzi G, Guaschino S.
Infant neurodevelopmental outcome in pregnancies complicated
by gestational hypertension and intra-uterine growth retardation.
J Perinat Med 1993; 21: 195-203.
4 Peacock JL, Cook DG, Carey IM, Jarvis MJ, Bryant AE,
Anderson HR, et al. Maternal cotinine level during pregnancy and
birth weight for gestational age. Int J Epidemiol 1998; 27:
647-56.
5 Chiaffarino F, Parazzini F, Paladini D, Acaia B, Ossola W, Marozio
L, et al. A small randomised trial of low-dose aspirin in women at
high risk of pre-eclampsia. Eur J Obstet Gynecol Reprod Biol
2004; 112: 142-4.
6 Pasanen M, Pelkonen O. The expression and environmental
regulation of P450 enzymes in human placenta. Crit Rev Toxicol
1994; 24: 211-29.
7 Holmes R, Montemagno R, Jones J, Rodeck C, Soothill P. Fetal
and maternal plasma insulin-like growth factors and binding
proteins in pregnancies with appropriate or retarded fetal growth.
Early Hum Dev 1997; 49: 7-17.
8 Syme MR, Paxton JW, Keelan JA. Drug transfer and metabolism
by the human placenta. Clin Pharmacokinet 2004; 43:
487-514.
9 Pasanen M. The expression and regulation of drug metabolism
in human placenta. Adv Drug Deliv Rev 1999; 38: 81-97.
10 Islam OM, Hara M, Miyake J. Induction of P-glycoprotein,
glutathione-S-transferase and cytochrome P450 in rat liver by
atrazine. Environ Toxicol Pharmacol 2002; 12: 1-6.
11 Lankas GR, Wise LD, Cartwright ME, Pippert T, Umbenhauer
DR. Placental P-glycoprotein deficiency enhances
susceptibility to chemically induced birth defects in mice. Reprod Toxicol
1998; 12: 457-63.
12 Smit JW, Huisman MT, Tellingen O, Wiltshire HR, Schinkel AH.
Absence or pharmacological blocking of placental
P-glycoprotein profoundly increases fetal drug exposure. J Clin Invest 1999;
104: 1441-7.
13 Younoszai MK, Peloso J, Haworth JC. Fetal growth retardation
in rat exposed to cigarette tobacco during pregnancy. Am J
Obstet Gynecol 1969; 104: 1027.
14 Li Y, Wang H, Li JF. In utero exposure to tobacco and alcohol
modifies neurobehavioral development in mice offspring:
Consideration a role of oxidative stress. Pharmacol Res 2004; 49:
467-73.
15 Kenagy J, Liu F, Soares M, Audus KL. Gestational and tobacco
effects on peptidase activity in the placenta. Peptides 1998; 19:
1659-66.
16 Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein
measurement with the Folin phenol reagent. J Biol Chem 1951; 193:
265-75.
17 Ondrejickova O, Horakova L, Juranek I, Ziegelhoeffer A, Stolc
S. Effect of stobadine on lipid peroxidation in brain and heart
after ischemia and reperfusion of the brain. Life Sci 1999; 65:
1959-61.
18 Wang H, Peng RX, Kong R, Zeng HG. Effect of allicin on
ethanol-induced hepatotoxicity in mice. Wei Sheng Yan Jiu 1998;
27: 415-7.
19 Wang H, Peng RX, Wang RK, Kong R. Antagonizing effect of
sodium ferulate on the changes of hepatic antioxidative function
induced by ethanol in mice. Acta Pharm Sin 1997; 32: 511-4.
20 Morris DL, Davila JC. Analysis of rat cytochrome P450
isoenzyme expression using semi- quantitative reverse
transcriptase-polymerase chain reaction (RT-PCR). Biochem Pharmacol 1996;
52: 781-92.
21 Kwan P, Sills GJ, Butler E, Gant TW, Brodie MJ. Differential
expression of multidrug resistance genes in naive rat brain.
Neurosci Lett 2003; 339: 33-6.
22 Cavicchioli L, Flanigan TP, Dickson JG, Vantini G, Dal Toso R,
Fusco M, et al. Choline acetyltransferase messenger RNA
expression in developing and adult rat brain: Regulation by nerve
growth factor. Brain Res Mol Brain Res 1991; 9: 319-25.
23 Chatelain P. Children born with intra-uterone growth
retardation (IUGR) or small for gestational age (SGA): Long term growth
and metabolic consequences. Endocr Regul 2000; 34: 33-6.
24 Gupta RC, Sastry BV. Toxicology of the placenta. In: Ballantyne
B, Marrs TC, Syversen T, editors. General and applied toxicology.
London: MacMillan; 2000. p 1233-63.
25 Whitlock JP. Induction of cytochrome P4501A1. Annu Rev
Pharmacol Toxicol 1999; 39: 103-25.
26 Wu J, Ramesh A, Nayyar T, Hood DB. Assessment of
metabolites and AhR and CYP1A1 mRNA expression subsequent to
prenatal exposure to inhaled benzo(a)pyrene. Int J Dev Neurosci
2003; 21: 333-46.
27 Takagi Y, Nikaido T, Toki T, Kita N, Kanai M, Ashida T,
et al.
Levels of oxidative stress and redox-related molecules in the
placenta in preeclampsia and fetal growth restriction. Virchows
Arch 2004; 444: 49-55.
28 Schinkel AH, Mayer U, Wagenaar E, Mol CA, van Deemter L,
Smit JJ, et al. Normal viability and altered pharmacokinetics in
mice lacking mdr1-type (drug-transporting) P-glycoproteins.
Proc Natl Acad Sci USA 1997; 94: 4028-33.
29 Lin JH. Drug-drug interaction mediated by inhibition and
induction of P-glycoprotein. Adv Drug Deliv Rev 2003; 55: 53-81.
30 Novotna M, Libra A, Kopecky M, Pavek P, Fendrich Z, Semecky
V, et al. P-glycoprotein expression and distribution in the rat
placenta during pregnancy. Reprod Toxicol 2004; 18:
785-92.
31 Lee CH. Induction of P-glycoprotein mRNA transcripts by
cycloheximide in animal tissues: Evidence that class I Pgp is
transcriptionally regulated whereas class II Pgp is posttranscriptionally
regulated. Mol Cell Biochem 2001; 216: 103-10.
32 Lee CH. Differential regulation of P-glycoprotein genes in
primary rat hepatocytes by collagen sandwich and drugs. J Cell
Biochem 2002; 86:12-20.
33 Gottesman MM. How cancer cells evade chemotherapy:
sixteenth Richard and Hinda Rosenthal Foundation Award Lecture.
Cancer Res 1993; 53: 747-54.
34 Doi AM, Holmes E, Kleinow KM. P-glycoprotein in the catfish
intestine: inducibility by xenobiotic and functional properties.
Aquat Toxicol 2001; 55: 157-70.
|
Copyright©APS 2006 Add: 294 Tai-Yuan Road,Shanghai 200031,China Phn: 86-21-5492-2821 Fax: 86-21-5492-2823 E-mail: aps@mail.shcnc.ac.cn |
