3-Methyl-4-nitrophenol metabolism by uridine diphosphate glucuronosyltransferase and sulfotransferase in liver microsomes of mice, rats, and Japanese quail (Coturnix japonica)

Article abstract of DOI:10.1897/07-034R1.1

3-Methyl-4-nitrophenol (PNMC) is a component of diesel exhaust particles and one of the major breakdown products of the insecticide fenitrothion. This chemical has a high potential for reproductive toxicity in Japanese quail (Coturnix japonica) and rats.

Full text of DOI:10.1897/07-034R1.1

Environmental Toxicology and Chemistry, Vol. 26, No. 9, pp. 1873–1878, 2007
2007 SETAC
Printed in the USA
0730-7268/07 $12.00 .00
᭧
ϩ
3-METHYL-4-NITROPHENOL METABOLISM BY URIDINE DIPHOSPHATE
GLUCURONOSYLTRANSFERASE AND SULFOTRANSFERASE IN LIVER
MICROSOMES OF MICE, RATS, AND JAPANESE QUAIL (COTURNIX JAPONICA
)
C
HUL-H
O
L
EE,† MICHIHIRO
K
AMIJIMA,† CHUN
M
EI
L
I
,ठSHINJI
T
ANEDA,࿣ AKIRA K. SUZUKI,࿣ and
T
AMIE
NAKAJIMA*†
†Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, 65 Tsurumaicho,
Showa-ku, Nagoya, Aichi 466-8550, Japan
‡Department of Basic Veterinary Science, The United Graduate School of Veterinary Science, Gifu University, Gifu 501-1193, Japan
§Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and
Technology, Tokyo 183-8509, Japan
࿣
Environmental Nanotoxicology Section, Research Center for Environmental Risk, National Institute for Environmental Studies,
Ibaraki 305-8506, Japan
(
Received 16 January 2007; Accepted 27 March 2007)
Abstract—3-Methyl-4-nitrophenol (PNMC) is a component of diesel exhaust particles and one of the major breakdown products
of the insecticide fenitrothion. This chemical has a high potential for reproductive toxicity in Japanese quail (Coturnix japonica
)
and rats. Because PNMC inhaled by the body is metabolized by uridine diphosphate glucuronosyltransferase (UGT) and sulfo-
transferase, we investigated these enzyme activities in the hepatic microsomes and cytosols of quail (as a model of wild birds) and
compared these activities with those of rats and mice as models of ecological and human risk assessment. The maximum velocity
of the UGT for PNMC in quail was 12.7 nmol/min/mg, which was one third and one fourth those of rats and mice, respectively.
The Michaelis–Menten constant of UGT for PNMC in quail was 0.29 mM, which was 1.3- and 1.8-fold higher than that in mice
and rats, respectively, but not significantly different. In accordance with these results, UGT activities for PNMC were lowest in
quail, with those in mice and rats being 4.4- and 2.7-fold higher, respectively. Sulfotransferase activity for PNMC was considerably
less than that of UGT in all animals, including quail; no significant differences in the activities were found among mice, rats, and
quail. These results suggest that glucuronidation may be involved primarily in PNMC elimination from wild birds as well as
mammals and that the UGT activity in quail is less than that in the rodents.
Keywords—3-Methyl-4-nitrophenol
Diesel exhaust particles
Fenitrothion
Glucuronosyltransferase activity
Sul-
fotransferase activity
INTRODUCTION
thion is widely used as an organophosphorous insecticide,
mainly in agriculture for controlling chewing and sucking in-
sects on rice, cereals, fruits, vegetables, stored grains, and
cotton. Fenitrothion also is used in public health programs as
well as indoors for the control of flies, mosquitoes, and cock-
roaches [18]. After exposure and subsequent absorption into
the body, this pesticide is rapidly metabolized. The main me-
tabolites for this compound are alkyl phosphates, such as di-
methyl thiophosphate and dimethyl phosphate, and the phe-
nolic compound PNMC [19]. 3-Methyl-4-nitrophenol is ex-
creted in urine in the form of conjugates with glucuronic or
sulfuric acid, producing the corresponding glucuronide
(3-methyl-4-nitrophenol glucuronide [PNMCG]) and sulfate
(3-methyl-4-nitrophenol sulfate [PNMCS]). The conjugations
of PNMC are catalyzed by uridine diphosphate glucuronosyl-
transferase (UGT) [20] and sulfotransferase (SULT), respec-
tively [21].
The use of diesel engines is steadily increasing because of
their superior fuel efficiency and efforts toward decreasing
engine exhaust emissions over the past 20 years [1]. Diesel
exhaust emissions, however, contain fine particulate matter
composed of carbon-based particles that adsorb various or-
ganic compounds, including polycyclic aromatic hydrocarbons
(PAHs), quinones, and nitro-PAHs [2]. Many of these organic
compounds associated with diesel exhaust particles (DEPs) are
known to be carcinogenic [3] and mutagenic in rodents [4].
Diesel exhaust particles also can lead to potential adverse ef-
fects on both the male and female reproductive systems in
rodents [5–8]. Thus, air pollution caused by DEPs may be
associated with adverse health effects in humans, including
lung cancer [9,10], allergic rhinitis [11,12], and bronchial asth-
ma–like diseases [13,14]. Recently, four nitrophenol deriva-
tives—4-nitrophenol, 2-methyl-4-nitrophenol, 3-methyl-4-ni-
Recently, PNMC has been reported to exhibit estrogenic
and antiandrogenic activity in vitro and in vivo in rats [15,22–
24]. In addition, this compound induced impairment of testic-
trophenol (4-nitro-m-cresol [PNMC]), and 4-nitro-3-phenyl-
phenol—were isolated from DEPs [15,16]. It is of genuine
interest to understand which chemicals can potentially lead to
adverse effects in rodents or humans.
ular function in adult male Japanese quail (Coturnix japonica
)
[25] as well as male rats [26]. In the quail, a 78-mg/kg dose
administered singly significantly decreased plasma testoster-
one levels by half compared with those in the untreated group,
whereas in the rats, a 100-mg dose given consecutively for 5
days decreased plasma testosterone level by the same level as
3-Methyl-4-nitrophenol also is formed via both metabolism
and environmental degradation of fenitrothion [17]. Fenitro-
* To whom correspondence may be addressed
(tnasu23@med.nagoya-u.ac.jp).
1873

1874
Environ. Toxicol. Chem. 26, 2007
C.-H. Lee et al.
in quail. Although the direct comparison of the adverse effects
of PNMC in the two methodologically different studies is dif-
ficult, quail may be more vulnerable to the adverse effects on
the reproductive system than rats. Here, one question may be
raised about the species difference seen in the reproductive
toxicity for PNMC. Because species differences were noted
in UGT and SULT activities [27], it should be clarified whether
those also are seen in these enzyme activities for PNMC among
other species, such as mice, rats, and quail. Humans are at risk
of exposure to PNMC as well; therefore, it is very important
to determine the kinetic parameters as well as the species
difference in quail as well as in rats or mice, which often are
used as experimental animals for ecological and human risk
assessment.
The aim of the present study was to determine UGT and
SULT activities for PNMC in liver microsomes and cytosols
in Japanese quail and in mice and in rats, respectively. The
results of this investigation served to elucidate whether the
differences in UGT activity for PNMC among quail and mice
or rats might reflect varying degrees of susceptibility to re-
productive toxicity in birds and/or mammals.
Fig. 1. Chromatograms of 3-methyl-4-nitrophenol and 3-methyl-4-
nitrophenol glucuronide reaction products with and without uridine
5Ј-diphosphate glucuronic acid and with and without ␤-glucuronidase,
respectively, in mouse liver microsome. (A) Chromatogram of 3-meth-
yl-4-nitrophenol reaction products in incubation mixture without uri-
dine 5
of 3-methyl-4-nitrophenol reaction products in incubation mixture
with uridine 5 -diphosphate glucuronic acid for 10 min. Peak 1 is 3-
Ј-diphosphate glucuronic acid for 10 min. (B) Chromatogram
MATERIALS AND METHODS
Ј
methyl-4-nitrophenol, and peak 2 is a new metabolite peak thought
to be 3-methyl-4-nitrophenol glucuronide. (C) Chromatogram after
Chemicals
3-Methyl-4-nitrophenol was purchased from Tokyo Kasei
Kogyo (Tokyo, Japan). Acetonitrile, methanol, and acetic acid
(high-performance liquid chromatography [HPLC] grade), and
incubation of 3-methyl-4-nitrophenol glucuronide without
ronidase for 1 h. (D) Chromatogram after incubation of 3-methyl-4-
nitrophenol glucuronide with -glucuronidase for 1 h.
␤-glucu-
␤
uridine 5
chased from Wako Pure Chemical (Osaka, Japan) and 3
phoadenosine 5 -phosphosulfate (PAPS) and -glucuronidase
Ј
-diphosphate glucuronic acid (UDPGA) were pur-
Ј
-phos-
the microsomal pellets were resuspended in the buffer to pro-
vide a protein content of 10 mg/ml and then used to determine
UGT activity. Protein contents were measured by the Bio-Rad
protein assay (Bio-Rad Laboratories, Hercules, CA, USA) with
bovine serum albumin as the standard.
Ј
␤
from Sigma-Aldrich Co. (St. Louis, MO, USA).
Experimental animals
In the present study, mice and rats were used according to
the Guidelines for Animal Experiments of the Nagoya Uni-
versity Animal Center, and the use of quail was approved by
the Animal Care and Use Committee of the Japanese National
Institute for Environmental Studies. Eight-week-old male
C57BL6/N mice and eight-week-old male Sprague-Dawley
rats were purchased from Clea Japan (Tokyo, Japan). Six-
week-old male Japanese quail (C. japonica) and their food
were provided by Kanematsu Quail Diet (Kanematsu Agri-
tech, Ibaraki, Japan). Mice and rats were housed in cages in
Analysis of UGT activity
The UGT activity for PNMC was determined according to
the method described by Elovaara et al. [28] with a slight
modification. A metabolite of PNMC with UGT was deter-
mined by HPLC. Fifty micrograms of hepatic microsomal pro-
tein were preincubated with 10
37ЊC for 5 min. The incubation mixture (final volume, 250
␮
l of 0.125% Triton X-100 at
l)
␮
consisted of 50 mM Tris-HCl buffer (pH 7.4), 4 mM MgCl2,
0.12 mM KCl, 0.5 mM PNMC, and preincubated microsomes.
a clean room under controlled temperature (23–25ЊC), relative
The reaction was started with 10
vial) or autoclaved distilled water (reference vial). After in-
cubation for 10 min at 37 C, the reaction was stopped by
adding 250 l of ice-cold acetonitrile. The reaction samples
were then placed in an ice bath for 10 min before centrifugation
at 10,000 for 5 min. The resulting supernatants were injected
into a HPLC system (Hitachi, Tokyo, Japan) equipped with a
Wakopak Wakosil-II 5C18-100 column (film thickness, 5 m;
inner diameter, 4.6 mm; length, 150 mm; Wako Pure Chemical,
Osaka, Japan), L6000 pump, AS-2000 autosampler, L7300 col-
umn oven, L4200 UV-Vis detector (at 300 nm), and D-2500
integrator. Acetonitrile with 0.2% acetic acid in Millipore wa-
ter (35:65 v/v) was used as the mobile phase at a flow rate of
1 ml/min. Under these conditions, the peaks of PNMCG (a
metabolite of PNMC) and PNMC appeared at 2.9 and 9.2 min,
respectively (Fig. 1A and B), and the formation of PNMCG
as well as the amount of reduced PNMC were linearly in-
␮l of 50 mM UDPGA (sample
humidity (57–60%), and light (lights-on, 9:00 AM to 11:00
PM). Quail (age, six to nine weeks) were housed in metal
cages in a controlled environment (lights-on, 5:00 AM to
Њ
␮
7:00 PM; temperature, 23
Ϯ 2ЊC; humidity, 50 Ϯ 10%; air
exchanged 20 times hourly). Rodents and quail were killed at
10 and 9 weeks of age, respectively. Liver was removed and
g
stored at
Ϫ85ЊC until used. Mean body and liver weights were
␮
23.9 and 1.22, 351.2 and 13.3, and 133.6 and 2.15 g in mice,
rats, and quail, respectively.
Preparation of microsomes and cytosol from liver
The livers were homogenized in three volumes (w/v) of
0.25 M sucrose and 10 mM phosphate buffer (pH 7.4) with
an ultrasonic cell disrupter (Yamato Scientific, Tokyo, Japan).
Enzyme fractions were prepared at 4
centrifugation: The supernatant of the first centrifugation at
10,000 for 10 min was further centrifuged at 105,000 for
ЊC by differential ultra-
g
g
1 h to obtain the microsomal and cytosolic fractions. The cy-
tosols were used for the measurement of SULT activity, and
creased with the incubation time (
Յ30 min) and protein con-
centration (0–200 g/250 l). The UGT activity (nmol/min/
␮
␮

3-Methyl-4-nitrophenol metabolism by UGT and SULT
Environ. Toxicol. Chem. 26, 2007
1875
mg protein) was calculated as follows: Substrate amounts add-
ed (PNMC [nmol])·(peak area for PNMC in the reference vial
test. Differences with p values of less than 0.05 were consid-
ered to be statistically significant.
Ϫ
that in sample vial)/peak area for PNMC in reference vial/
RESULTS
incubation time (10 min)/microsomal protein (50 g). In this
␮
equation, the difference between PNMC amount in the ref-
erence vial and in the sample vial corresponds to that of
PNMCG produced.
To identify the PNMC metabolite peak on the chromato-
gram in Figure 1B as PNMCG, HPLC elutions from 2.5 to
3.5 min after the sample injection were collected. The collected
fraction was dried and resolved in an aliquot of Tris-HCl buffer
(pH 7.4). Then, the resolved solution was buffered with sodium
acetate buffer (pH 5.0) and hydrolyzed enzymatically using
PNMCG characterization
When comparing the chromatograms of the reaction mix-
tures for measuring the UGT activity of PNMC with and with-
out UDPGA, a new metabolite peak appeared only in the for-
mer at a retention time of 2.9 min (Fig. 1B). For identification
of the new peak, the fraction from 2.5 to 3.5 min with a peak
at 2.9 min was collected and measured as described in Ma-
terials and Methods. The chromatograms of the fraction in-
cubated without and with ␤-glucuronidase are shown in Fig.
␤
-glucuronidase at 37
Њ
C for 1 h (hydrolyzed sample). As a
-glucuroni-
1C and D, respectively. After hydrolysis, the peak at 2.9 min
completely disappeared, to be replaced by the appearance of
a peak corresponding to PNMC at 9.2 min. These results sug-
gest that the new peak at 2.9 min is the glucuronidation product
of PNMC (i.e., PNMCG).
reference, another resolved solution without the
␤
dase was incubated under the same conditions (nonhydrolyzed
sample). After ice-cold acetonitrile was added to the hydro-
lyzed and nonhydrolyzed samples, both samples were centri-
fuged at 10,000
g for 10 min and then analyzed using the
HPLC method described above.
UGT kinetics
The Km and Vmax of UGT activity for PNMC were calculated
from Lineweaver-Burk plots (Fig. 2 and Table 1). The Vmax in
quail was 12.7 nmol/min/mg, which was one third and one
fourth that in rats and mice, respectively. The mean Km of
UGT for PNMC in quail was 0.29 mM, which was 1.3- and
1.8-fold higher than the mean Km in mice and rats, respectively.
No significant difference, however, was found between them.
As a result, the Vmax to Km ratio for PNMC was the smallest
in quail, followed by rats and then mice.
Analysis of SULT activity
The SULT activity for PNMC was determined according
to the method described by Yodogawa et al. [29] with a slight
modification. The reaction mixture consisted of 100
hepatic cytosolic protein, 50 mM Tris-HCl buffer (pH 7.4), 5
mM MgCl2, and 200 M PAPS in a final volume of 250
(sample vial). 3 -Phosphoadenosine 5 -phosphosulfate was
omitted from the mixture for controls (reference vial). The
reaction was started with 2.5 l of PNMC (0.25 mM) and
incubated at 37 C for 10 min. After the reaction was stopped
by the addition of 250 l of ice-cold acetonitrile, the reaction
tubes were placed in an ice bath for 10 min, followed by
centrifugation at 10,000 for 5 min. The resulting supernatants
␮g of
␮
␮l
Ј
Ј
␮
Њ
UGT activity for PNMC
␮
The UGT activities for PNMC in hepatic microsomes of
mice, rats, and quail are shown in Table 2. The activity was
the lowest in quail, whereas the activities in mice and rats were
4.4- and 2.7-fold higher, respectively.
g
were analyzed using the HPLC method described above. Be-
cause the SULT activity for PNMC was barely discernible, we
could not detect the PNMCS peak on the chromatogram.
Therefore, the presence of SULT activity was analyzed only
by measuring the disappearance of PNMC concentrations after
incubation (i.e., the difference between the PNMC peak area
of reference vial and that of samples after incubation). Thus,
the activity (nmol/10 min/mg protein) was calculated as the
amount of substrate that disappeared during the incubation
time (10 min) per cytosol protein content by a method similar
to the one described in connection with UGT activity.
SULT activity for PNMC
The SULT activity for PNMC in the hepatic cytosols of
mice, rats, and quail shown in Table 3 was considerably less
than that of UGT in all the animals, including quail. No sig-
nificant differences in that activity were found among mice,
rats, and quail.
DISCUSSION
A statistical difference in UGT activity for PNMC was seen
among mice, rats, and quail. The fact that the Km values did
not differ among them, whereas the Vmax values were lower in
birds than in rodents, suggested that the affinity of PNMC for
UGT is no different between rodents and birds but that the
constitutive expression of the enzyme is lower in birds than
in rodents. Thus, the Vmax to Km ratio (often referred to as an
index of intrinsic clearance) was the smallest in quail, but the
ratios were almost the same between mice and rats. Short et
UGT kinetics
Uridine diphosphate glucuronosyltransferase activity for
PNMC was measured in duplicate determination using three
individual liver microsomes of mice, rats, and quail and dif-
ferent concentrations of PNMC (0.1, 0.2, 0.25, 0.33, 0.5, 1.0,
and 2.5 mM). Incubation conditions were chosen so that the
product formation was linear with respect to both the amount
of microsomal protein (50
min). Using the mean values of the UGT activity obtained
against each substrate concentration, the maximum velocity
␮g) and the incubation time (10
al. [27] reported species differences in UGT activity: For
nitrophenol, the activity was the highest in goats (14.28
p-
Ϯ
6.73 nmol/mg protein/min), followed by rats (2.61
Ϯ 1.26
(
Vmax), and Michaelis constant (Km), the values for PNMC were
nmol/mg protein/min) and then chickens (1.65 1.01 nmol/
Ϯ
calculated from Lineweaver-Burk plots.
mg protein/min). These results suggest that there may be a
species difference in UGT activity for another nitrophenol.
The above report concerning species difference in activity is
so limited, however, that it is doubtful whether this difference
can be generalized to all substrates of UGT. In contrast with
Statistical analysis
Statistical differences between group mean values were de-
termined by the Kruskall-Wallis test or Wilcoxon rank-sum

1876
Environ. Toxicol. Chem. 26, 2007
C.-H. Lee et al.
Table 2. 3-Methyl-4-nitrophenol glucuronidation activity in hepatic
microsomes from mouse, rat, and quaila
Glucuronidation activity
(nmol/min/mg protein)
n
Mouse
Rat
Quail
5
5
6
30.2
18.8
6.9
Ϯ
Ϯ
Ϯ
2.4
1.2b
1.4bc
a Values are presented as the mean
group.
Ϯ standard deviation for each
b Significantly different from mouse (
p
Ͻ
0.01).
c Significantly different from rat (
p Ͻ 0.01).
PNMC has potentially adverse effects on the reproductive sys-
tem in quail [25] as well as in rats [26], suggesting the need
to examine whether this potential is truly stronger in quail than
in rats. Such a study may show the identity of the genuine
toxic substance in PNMC.
Alarming levels of DEPs are spewed into the environment
in many countries. Each year, 58,902 tons of DEPs in Japan
[30], 111,530 tons in the United States [31], 37,000 tons in
the United Kingdom [32], and 240,000 tons in the rest of the
European Union [33] are emitted. One kilogram of DEP con-
tains 28 mg of PNMC [15,16], suggesting that 1,036 to 6,720
kg of PNMC are potentially emitted into the global environ-
ment annually. In fact, Morville et al. [34] reported a PNMC
mean concentration of 0.69 ng/m3 (maximum, 5.03 ng/m3) in
air samples collected in urban, suburban, and rural sites in
France. Yoshida et al. [6] reported that a DEP dose of 3 mg/
m3 in ICR mice induced the degeneration of Leydig cells and
reduced daily sperm production after 12 h of exposure over 6
months. Watanabe and Oonuki [5] reported that exposure (6
h/d for 5 d/week) to DEP containing 5.63 mg/m3 of particulate
matter, 4.10 ppm of nitrogen dioxide, and 8.10 ppm of nitrogen
oxide from birth to three months suppressed testicular function
in male rats, as evidenced by a decrease in their sperm pro-
duction. In contrast, exposure to 1 or 3 mg/m3 of DEP for
eight months did not affect sperm production in Fischer 344
rats but did significantly elevate serum and testicular testos-
terone [7]. Although estimating the exact PNMC dose is dif-
ficult in such experiments, the PNMC contained in the DEPs
may be one of the toxicants inducing reproductive toxicity.
3-Methyl-4-nitrophenol also is a degraded product of fen-
itrothion, an organophosphorous insecticide that is used world-
wide. The amount of fenitrothion released into the environment
in Japan was approximately 1,300 tons in 2002, and roughly
half was degraded into PNMC [35]. Asman et al. [36] reported
that the median concentrations of PNMC in rainwater were 83
and 89 ng/L at the Danish Roskilde and Oure agricultural
stations, respectively, and that fenitrothion was identified as
the main source. Baroja et al. [37] also reported that PNMC
was detected at a concentration of 24.1 ng/m3 on the sixth day
Fig. 2. Lineweaver-Burk plot of uridine diphosphate glucuronosyl-
transferase activity for 3-methyl-4-nitrophenol using hepatic micro-
somes from mouse (A), rat (B), and quail (C). Vmax
ϭ maximum
velocity; [S] concentration of 3-methyl-4-nitrophenol.
ϭ
UGT activity, no significant difference was found in SULT
activity among mice, rats, and quail. In addition, the SULT
activity was only one tenth the UGT activity, suggesting that
the latter is a major conjugation enzyme for PNMC. The
Table 1. Kinetic parameters for 3-methyl-4-nitrophenol glucuronidation activity in hepatic microsomes from mouse, rat, and quaila
Maximum
Michaelis–Menten
constant (mM)
Maximum velocity
(nmol/min/mg protein)
velocity/Michaelis–Menten
constant
n
Mouse
Rat
Quail
3
3
3
0.22
0.16
0.29
Ϯ
Ϯ
Ϯ
0.05
0.02
0.04
50.8
31.8
12.7
Ϯ
Ϯ
Ϯ
4.3
2.2
0.9
232.6
196.1
44.6
Ϯ
Ϯ
Ϯ
29.7
16.9
8.2
a Values are presented as the mean
Ϯ standard deviation for each group.

3-Methyl-4-nitrophenol metabolism by UGT and SULT
Environ. Toxicol. Chem. 26, 2007
1877
Table 3. 3-Methyl-4-nitrophenol sulfation activity in hepatic cytosol
from mouse, rat, and quaila
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5
5
6
9.1
10.3
6.2
Ϯ
Ϯ
Ϯ
3.2
4.8
2.2
a Values are presented as the mean
group.
Ϯ standard deviation for each
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and 54.7 ng/m3 in the second week after fenitrothion was
sprayed in forests in Spain. These findings clearly indicate that
large amounts of PNMC may be emitted into the environment
in the form of fenitrothion degradation products. Thus, both
DEP- and fenitrothion-derived PNMC need to be taken into
consideration when assessing the environmental risk of
PNMC.
The present study suggests that the UGT plays an important
role in PNMC elimination in vivo not only in quail but also
in mice and rats. Whether UGT activity in humans is similar
to that in quail, rats, or mice remains unknown. Uridine di-
phosphate glucuronosyltransferases comprise a multigenetic
family. The genetic polymorphisms of UGT isoforms are of
potentially toxicological, pharmacological, and physiological
significance. At least 14 functional UGT isozymes have been
identified in humans. Genetic polymorphisms have been iden-
tified for the following 12 isozymes: UGT1A1, UGT1A3,
UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT2A1,
UGT2B4, UGT2B7, UGT2B15, and UGT2B28 [38]. The ge-
netic polymorphism may affect the rates of glucuronidation
and, thereby, influence the risk of an individual to develop
chemical-induced toxicity [39,40]. The activity of PNMC for
each isozyme of human UGT and the effect of polymorphisms
on the activity have to be investigated to know the risk from
PNMC in humans exposed to DEPs or fenitrothion sources.
In conclusion, this article provides the first experimental
evidence on the UGT activity for PNMC, an activity that is
lowest in quail, followed by rats and then mice. The relevance
of different UGT activities to the risk assessment of PNMC-
related compounds from the viewpoint of their reproductive
toxicity needs to be further explored.
20. Mackenzie PI, Owens IS, Burchell B, Bock KW, Bairoch A, Be-
langer A, Fournel-Gigleux S, Green M, Hum DW, Iyanagi T,
Lancet D, Louisot P, Magdalou J, Chowdhury JR, Ritter JK,
Schachter H, Tephly TR, Tipton KF, Nebert DW. 1997. The UDP
glycosyltransferase gene superfamily: Recommended nomencla-
ture update based on evolutionary divergence. Pharmacogenetics
7:255–269.
Acknowledgement—This work was supported, in part, by a Grant-in-
Aid for Scientific Research from the Japan Society for the Promotion
of Science, Japan (17310033).
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