TOXICOLOGICAL SCIENCES 82, 374380 (2004)

doi:10.1093/toxsci/kfh286
Advance Access publication September 29, 2004

Enhanced Acetaminophen Toxicity by Activation of the

Pregnane X Receptor
Grace L. Guo,*,1 Jeff S. Moffit,,1 Christopher J. Nicol,* Jerrold M. Ward, Lauren A. Aleksunes, Angela L. Slitt,
Steven A. Kliewer, Jose E. Manautou and Frank J. Gonzalez*,2
*Laboratory of Metabolism, CCR, NCI, NIH, Bethesda, Maryland; Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut;
Veterinary and Tumor Pathology Section, Center for Cancer Research, NCI, Frederick, Maryland; Department of Pharmacology,
Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas; and Department of Pharmacology,
University of Texas Southwestern Medical Center, Dallas, Texas
Received August 24, 2004; accepted August 25, 2004

The pregnane X receptor (PXR) is a ligand-activated transcription factor and member of the nuclear receptor superfamily. Activation of PXR represents an important mechanism for the
induction of cytochrome P450 3A (CYP3A) enzymes that can
convert acetaminophen (APAP) to its toxic intermediate metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Therefore, it was
hypothesized that activation of PXR plays a major role in APAPinduced hepatotoxicity. Pretreatment with the PXR activator,
pregnenolone 16a-carbonitrile (PCN), markedly enhanced APAPinduced hepatic injury, as revealed by increased serum ALT
levels and hepatic centrilobular necrosis, in wild-type but not
in PXR-null mice. Further analysis showed that following PCN
treatment, PXR-null mice had lower CYP3A11 expression,
decreased NAPQI formation, and increased maintenance of hepatic glutathione content compared to wild-type mice. Thus, these
results suggest that PXR plays a critical role in APAP-induced
hepatic toxicity, probably by inducing CYP3A11 expression and
hence increasing bioactivation.
Key Words: PXR; acetaminophen; hepatotoxicity; nuclear
receptor.

Acetaminophen (APAP) overdose is the leading cause of

drug-induced acute liver failure requiring transplantation in
the U.S. (Ostapowicz et al., 2002). Under prescribed dosing,
the majority of acetaminophen is rapidly metabolized by
phase II glucuronide and sulfate conjugation enzymes in the
liver to nontoxic compounds, followed by renal and biliary
excretion. However, a relatively minor metabolic pathway
includes bioactivation by phase I cytochrome P450 (CYP)
enzymes, such as CYP2E1, isoforms of CYP3A and
CYP1A2, to the highly reactive intermediate metabolite
N-acetyl-p-benzoquinone-imine (NAPQI) (Dahlin et al.,
1984; Gonzalez and Kimura, 2003). NAPQI has an extremely
1

These two authors contributed equally.

To whom correspondence should be addressed at Bldg. 37, Rm
3106B, CCR, NCI, NIH, Bethesda, MD 20892. Fax: (301) 496-8419.
E-mail: fjgonz@helix.nih.gov.
2

Toxicological Sciences vol. 82 no. 2

short half-life and under normal physiological conditions is

rapidly excreted after conjugation with glutathione (GSH), a
reaction carried in part by glutathione S-transferase (GST),
such as GSTp (Mitchell et al., 1973). The resulting conjugate
(APAP-GSH) can be further metabolized to APAP-cystein/
cysteinylglycine (APAP-Cys/Gly) and APAP-mercapturate
(APAP-Nac) (Gregus et al., 1988). However, when an overdose
occurs, the major metabolic pathways of elimination become
saturated, leading to both increased bioactivation of APAP and
formation of NAPQI, as well as depletion of cellular GSH. In the
absence of prevention, excess NAPQI may result in cell death
and hepatotoxicity due to covalent binding to essential cellular
macromolecules and/or other mechanisms such as oxidative
stress (Jollow et al., 1974).
Isoforms of CYP3A may play an important role in metabolizing acetaminophen to its toxic intermediate metabolite,
NAPQI. The kinetics of NAPQI formation by reconstituted
human liver CYP3A4 is compatible with the therapeutic doses
of this drug (Thummel et al., 1993), indicating that CYP3A4
is involved in APAP metabolism. Inducers of CYP3A potentiate, while inhibitors of CYP3A prevent, APAP toxicity
(DiPetrillo et al., 2002; Madhu et al., 1992; Sinclair et al.,
1998; van Bree et al., 1989). However, the role of CYP3A in
acetaminophen metabolism still remains controversial as
revealed by other studies in which CYP3A is negligible in
APAP metabolism in human, and CYP3A inducers protect
hamsters from APAP induced hepatic injury (Madhu and
Klaassen, 1991; Manyike et al., 2000). The CYP3A enzymes
metabolize over half of the pharmaceuticals on the current
market, and the expression levels of CYP3A enzymes are
modulated by a variety of xenobiotics, including numerous
chemicals and dietary compounds. Many of these chemicals
induce CYP3A by acting as ligands for the pregnane X receptor (PXR) in rodents or for the steroid xenobiotic receptor
(SXR), the PXR homologue in humans (Moore and Kliewer,
2000). PXR is a ligand activated transcription factor and
belongs to the orphan nuclear receptor superfamily. When

Society of Toxicology 2004; all rights reserved.

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ACTIVATING PXR ENHANCED APAP TOXICITY

activated, PXR induces a network of genes that encode phase I

and phase II xenobiotic metabolizing enzymes and drug
transporters by forming a heterodimer with the universal partner for class II nuclear receptors, retinoid X receptor (RXR),
which subsequently binds to the promoter or enhancer regions
of PXR target genes (Guo et al., 2002; Kliewer, 2003;
Kliewer et al., 1998; Lehmann et al., 1998). The activation
of PXR results in enhanced metabolism and/or excretion of
many endogenous chemicals or xenobiotics. The role of
orphan nuclear receptors in APAP metabolism was explored
and recent studies show that peroxisome proliferatorsactivated receptor a (PPARa) and the constitutive androstane
receptor (CAR) play roles in APAP induced hepatic injury
(Chen et al., 2000; Zhang et al., 2002).
In order to investigate the role of PXR in APAP-induced
hepatic toxicity, wild-type or PXR-null mice were pretreated
with pregnenalone 16a-carbonitrile prior to the administration
of a toxic dose of APAP. Pretreatment with PCN dramatically
augmented APAP-induced hepatic injury in wild-type, but not in
PXR-null mice. The severity of APAP toxicity correlated very
well with the levels of CYP3A11 expression. In summary,
the current study demonstrates an important role for PXR in
APAP-induced hepatic toxicity via induction of CYP3A11,
and therefore confirms that CYP3A11 is critical in APAP
reactive intermediate metabolite formation in mice.

authentic standards. Since this HPLC method does not separate the cysteinylglycine and cysteine conjugates of APAP, they were quantitated together
as APAP-CG/CYS. Preliminary chromatographic analysis of control urine
samples shows no interfering peaks. Quantitation was based on integrated
peak areas. The concentrations of APAP and its metabolites were calculated
using an APAP standard curve since the molar extinction coefficients of
APAP and its conjugated metabolites are approximately the same (Howie
et al., 1977).
Analysis of hepatic non-protein sulfhydryls (NPSH). Liver samples
obtained from mice killed at 6 h after APAP challenge were homogenized
(20% w/v) in 5% trichloroacetic acid/ethylenediamine tetraacetic acid (TCA/
EDTA). Homogenates were centrifuged at 1500 3 g for 15 min. NPSH concentration in supernatants was determined as an indicator of reduced glutathione (GSH) following the colorimetric procedure of Ellman (Boyne and
Ellman, 1972; Ellman, 1959). NPSH concentration was quantified by comparison with a GSH standard curve.
Northern blot analysis of gene expression. Total RNA was prepared
using Trizol reagent (Amersham Biosciences; Piscataway, NJ) and analyzed
by electrophoresis in 0.22 M formaldehyde-containing 1% agarose gel. The
sequences for the cDNA probes (CYP3A11, CYP2E1, CYP1A2, GSTp and
control 18s) are available upon request. Probes were 32P-labeled by the random
primer method using ready-to-Go DNA labeling beads (Amersham Biosciences,
Piscataway, NJ). The details for the Northern blot analysis have been described
in detail previously (Guo et al., 2003).
Histological analysis. Tissues were fixed in 10% phosphate buffered
formalin, and embedded in paraffin. Sections were prepared and stained with
hematoxylin and eosin, and subjected to a blind review by a pathologist.
Statistical analysis. The data were expressed as mean 6 SE. Statistical
significance was determined by one-way analysis of variance, followed by
Duncans posthoc test. The significance level was set at p 5 0.05.

MATERIALS AND METHODS

Chemicals. Acetaminophen and PCN were purchased from Sigma
(St. Louis, MO). The kit to measure alanine aminotransferase (ALT) was from
ThermoTrace (Melbourn, Australia) and the assay was carried out according to
the manufacturers instruction. Ten percent phosphate buffered formalin
was purchased from Fisher Scientific (Fair Lawn, NJ). Other reagents, unless
otherwise indicated, were obtained from Sigma.
Animals and treatments. Mice were housed in a pathogen-free animal
facility under standard 12-h light/12-h dark cycle with access to chow and
water ad libitum. All protocols and procedures were approved by the NCI
Animal Care and Use Committee and are in accordance with the National
Institute of Health and ALAC Guidelines. The 8- to 12-week-old male B6;
129-Pxrtm1GlaxoWellcome (PXR-null) mice or their corresponding wild-type controls were used throughout the study (n 5 5 to 7 per group). The animals were
pretreated with vehicle (corn oil, ip) or PCN (75 mg/kg, ip) for two days before
one APAP administration. APAP was dissolved in alkaline solution, and
delivered to animals at 350 mg/kg, ip.
Tissue collection (urine, serum, and liver). Pooled urine was collected
from five animals placed in metabolic cages for 6 h following the administration
of APAP. Blood was collected by orbital plexus bleeding at 6 and 24 h after
APAP administration. Serum was separated from whole blood by centrifugation
at 6000 3 g using Microcontainer serum separating tubes (Becton Dickinson,
Franklin Lakes, NJ). Following blood collection, the animals were euthanized.
Livers and kidneys were collected, divided and either stored in 10% phosphate
buffered formalin for histological analysis, or snap-frozen in liquid nitrogen and
stored at
80 C for future analysis.
Urinary analysis of APAP metabolites. Urine was analyzed for APAP
and its metabolites using an HPLC method modified from that of Howie et al.
(1977) as previously described (Manautou et al., 1996). Retention times of
APAP and its metabolites were determined by comparison with that of

RESULTS

Activation of PXR Potentiated APAP Hepatotoxicity

To determine the role of PXR in APAP-induced hepatic
toxicity, wild-type or PXR-null mice were pretreated with
PCN (75 mg/kg, ip for two days) followed by a single administration of APAP (350 mg/kg, ip). The degree of hepatic
injury was assessed by serum ALT levels obtained 6 and 24 h
following APAP administration (Fig. 1). In both wild-type and
PXR-null mice, the administration of APAP caused a timedependent elevation of ALT levels that was more severe in
PXR-null mice. However, APAP dramatically enhanced ALT
levels in wild-type mice (about 2-fold at 6 h and 6-fold at 24 h
after APAP administration) following pretreatment with PCN.
In contrast, following the APAP administration, the PXR-null
mice pretreated with PCN exhibited reduced ALT levels
compared to those pretreated with vehicles.
The degree of APAP-induced hepatic injury in wild-type
and PXR-null mice were also analyzed by histological analysis (Table 1). Typical acetaminophen toxicity in the liver is
manifested by centrilobular necrosis. Consistent with the
results obtained from analysis of serum ALT, pretreatment with PCN dramatically enhanced the acetaminophen
induced-hepatic injury (degeneration in the early stage and
necrosis in the late stage) in wild-type, but not in PXR-null

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GUO ET AL.

FIG. 1. Determination of ALT activities in serum of wild-type and PXRnull mice following PCN and APAP treatment. Wild-type or PXR-null mice
were pretreated with corn oil (CON) or PCN (75 mg/kg, ip, two days) before
administration of one dosage of APAP (350 mg/kg, ip). Blood was collected
and serum was separated as described in the Materials and Methods section.
ALT levels were measured according to the manufacturers instructions. The
black bars represent wild-type mice and the white bars represent PXR-null
mice. The statistical difference between vehicle and PCN pretreatment are
indicated by * for p 5 0.05; and ** for p 5 0.001.

TABLE 1
Hepatic Pathology in Wild-Type and PXR-Null Mice
Wild-type

Group
Control
PCN
APAP 6 h
PCN/APAP/6 h
APAP/24 h
PCN/APAP/24 h

PXR-null

Hepatocyte
degeneration

Hepatocyte
necrosis

Hepatocyte
degeneration

Hepatocyte
necrosis

1
11
111

1
1
1
111

1
1

1
1/

11
1

Note. Histological analysis of wild-type and PXR-null livers after PCN and
APAP treatment. The livers of wild-type and PXR-null mice with aforementioned treatments were harvested and histological evaluation was performed
following H & E staining. Key:
, none; 1/
, minimal degree of lesion; 1,
mild; 11, moderate; 111, severe.

mice. Since it has been well established that APAP may

cause renal injury, a histological analysis was also performed
on kidney samples from the aforementioned groups; however, no morphological differences were identified (data
not shown).

FIG. 2. Analysis of urinary APAP metabolites. After PCN pretreatment

and APAP administration, each group of wild-type or PXR-null mice (n 5 5)
was placed in a metabolic cage. Pooled urine was collected for 6 h and APAP
metabolites (APAP-Glu, APAP-Sulf, APAP-Cys/CysGly, and APAP-Nac)
were analyzed by the HPLC method described in the Materials and Methods
section.

Activation of PXR Enhanced Urinary Excretion of

APAP Metabolites
The APAP-metabolites are removed mainly by biliary and
urinary excretion (Gregus et al., 1988). Urinary excretion of
APAP metabolites not only reflects the fate of APAP, the
non-invasive nature of this procedure also makes urinary analysis of APAP metabolites a very attractive means to assess
acetaminophen metabolism, especially in the clinic. HPLC analysis of pooled urine was performed to identify any differences in
the profiles of APAP metabolites among wild-type and PXR-null
mice (Fig. 2). Consistent with the patterns observed with serum
ALT levels, PCN treatment of wild-type mice increased GSHderived APAP metabolites (APAP-Cys/CysGly and APAPNAC), compared to respective APAP alone groups (Fig. 2).
Presence of these metabolites in urine is reflective of NAPQI
formation in the liver. Also, similar to the patterns observed with
serum ALT levels, the urinary APAP-GSH metabolites among
vehicle pretreated PXR-null mice were higher than those in
vehicle pretreated wild-type mice (Fig. 2). However, pretreated
of PXR-null mice with PCN reduced the GSH-derived APAP
metabolites excreted into the urine comparable to, or lower than,
those seen among vehicle pretreated wild-type mice. Interestingly, the urinary excretion of detoxification metabolites
APAP-Gluc and APAP-Sulf was also increased in PCN
pretreated wild-type mice despite enhanced toxicity. This is
probably reflective of changes in APAP glucuronidation,

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ACTIVATING PXR ENHANCED APAP TOXICITY

FIG. 3. Effect of PCN and APAP administration on hepatic NPSH

content in wild-type and PXR-null mice. Mice were treated as described in
the Materials and Methods and liver were collected at 6 or 24 h after APAP
administration. Hepatic NPSH contents were measured. The statistical
difference between control and treated group was indicated as * for p 5 0.05.

sulfation and/or transport-mediated basolateral efflux of these

conjugates by PCN.
Pretreatment of PCN Enhanced Glutathione Depletion in
Wild-Type Mice, but Not in PXR-Null Mice
The APAP-induced hepatic injury is tightly associated with
hepatic glutathione depletion. Therefore, hepatic glutathione
content was measured in wild-type and PXR-null mice after
PCN and APAP treatment (Fig. 3). There were no differences
in endogenous hepatic GSH levels between control wild-type
and PXR-null mice. However, compared to respective control
mice, pretreatment with PCN significantly increased hepatic
GSH content of wild-type ( p 5 0.05) but not PXR-null mice.
In addition, 6 h after APAP administration, the hepatic GSH
content of PCN-pretreated wild-type ( p 5 0.05) but not PXRnull mice was significantly reduced compared either to respective vehicle-pretreated or control groups. By 24 h after APAP
administration, the hepatic GSH content of PCN-pretreated
wild-type mice had returned to baseline levels.
PXR-Mediated Induction of CYP3A11 Results in
APAP-Induced Hepatic Toxicity
The toxicity of APAP overdose is exerted by formation of
its intermediate metabolite, NAPQI, by CYP2E1, isoforms
of CYP3A and CYP1A2; whereas the detoxification of
NAPQI may be via conjugation with GSH conducted by glutathione S-transferase p (GSTp), even the role of GSTp in

NAPQI detoxification is not certain (Henderson et al., 2000).

To investigate the molecular mechanisms by which activation
of PXR enhanced APAP-induced hepatic toxicity, the hepatic
mRNA levels of the genes encoding these key enzymes were
determined by Northern blot analysis (Fig. 4). Compared with
wild-type mice, basal levels of CYP3A11 expression were
higher in PXR-null mice; however, they were resistant to the
PCN-induced dramatic induction of CYP3A11 as seen in the
wild-type mice. The expression levels of CYP2E1 were moderately reduced by APAP administration at both 6 h and 24 h in
both genotypes; however, they virtually disappeared at 24 h
after the administration of APAP in wild-type mice pretreated
with PCN, but not in PXR-null mice. The expression levels of
CYP1A2 were induced to a moderate degree by PCN and were
inhibited by APAP administration regardless of the genotypes or
the combination with PCN. The expression levels of hepatic
GSTp were induced by both APAP administration and PCN
treatment irrespective of genotype. Moreover, in PXR-null
mice, although the basal levels of GSTp expression were low,
it was induced by PCN to levels comparable to those detected in
wild-type livers.

DISCUSSION

The bioactivation of overdosed APAP by several phase I

P450 enzymes (CYP2E1, isoforms of CYP3A and CYP1A2)
to its reactive intermediate metabolite, NAPQI, leads to hepatic
toxicity. The role of CYP2E1 and CYP1A2 in NAPQI production
has been explored comprehensively, but that of CYP3A11 is
uncertain. The expression levels of CYP3A are induced by
numerous endogenous and exogenous chemicals, many of
which are ligands of the orphan nuclear receptor, PXR. To
investigate the role of PXR and CYP3A in APAP-induced
hepatic injury, wild-type or PXR-null mice were pretreated with
a potent PXR activator, PCN, followed by acute administration
of APAP. This study demonstrates for the first time that PXR
plays a critical role in APAP metabolism, mainly via induction of
CYP3A11 resulting in enhanced APAP reactive metabolite formation, thereby dramatically increasing the extent of APAPinduced hepatic injury in mice. Moreover, this study confirms
a pivotal role for CYP3A in metabolizing APAP to its
intermediate metabolite NAPQI in mice.
This study clearly shows that PXR plays a pivotal role in
modulating APAP metabolism. Several lines of evidence
have suggested that hepatic nuclear receptors are involved in
APAP-induced hepatotoxicity. For example, activation of peroxisomal proliferator-activated receptor a (PPARa) appears
to reduce the severity of APAP-induced hepatic injury through
induction of numerous genes involved in pathways such as
stress response, DNA damage repair, and cell cycle regulation
(Chen et al., 2000; Shankar et al., 2003). Similarly, APAP toxicity appears to be enhanced by phenobarbital (PB), which may
be attributed to the activation of CAR, which induces expression

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GUO ET AL.

FIG. 4. The effect of PCN on the hepatic gene expression levels in the wild-type and PXR-null mice after PCN and APAP administration. Hepatic tissue was
obtained at 6 and 24 h after APAP administration. Total RNA was isolated, the expression levels of CYP3A11, CYP2E1. CYP1A2 and GSTp were determined
by Northern Blot analysis. Each group consisted of data from three individual animals. CON represents for corn oil treatment, PCN for PCN treatment, AP/6 hr
for 6 h following APAP administration, P/AP/6 hr for pretreatment with PCN followed by 6 h after APAP administration, AP/24 hr for 24 h after APAP
administration, and P/AP/24 hr for pretreatment with PCN followed by 24 h after APAP administration.

of CYP3A and CYP1A2 that metabolize APAP to its reactive

intermediate metabolite (Zhang et al., 2002). Interestingly, treatment with androstanol, a specific CAR inhibitor but a modest
PXR ligand, abrogated APAP induced-hepatotoxicity in wildtype mice, but produced an even greater toxicity in the CAR-null
mice. This former study may be interpreted to suggest that while
CAR activation critically affects APAP induced-hepatotoxicity,
activation of PXR activity influences APAP hepatotoxicity
consistent with the results seen here. Modulating PXR activity
can result in a markedly different outcome for drug metabolism.
PXR is activated by numerous structurally unrelated compounds
(Kliewer et al., 1998) and its activation affects the expression of
a network of genes encoding critical enzymes or transporters
involved in hepatic and enteric drug metabolism (Kliewer,
2003). Thus it is reasonable to predict that drugdrug interactions are one of the consequences after modulating PXR activity
by endogenous or xenobiotic factors.
The data presented here clearly suggests that CYP3A11
is involved in APAP-induced hepatic toxicity in mice. The

expression levels of CYP3A11 correlated well with the severity of APAP-induced hepatic injury. For example, the basal
levels of CYP3A11 expression were higher in PXR-null mice
compared to wild-type mice, and correlated with a more
severe APAP-induced hepatic toxicity as revealed by serum
ALT levels and the appearance of hepatic centrilobular necrosis. Although the role of GSTp in NAPQI detoxification
remains controversial, the reduced levels of GSTp in the
livers of PXR-null mice may also contribute to the more
severe APAP-induced hepatic injury. The CYP2E1 and
CYP1A2 enzymes are reported the two major forms of
P450s for the generation of NAPQI (Lee et al., 1996;
Tonge et al., 1998; Zaher et al., 1998), but there are studies
suggesting that other mechanisms of bioactivation exist. For
example, the CYP2E1-null mice are resistant to APAP toxicity even at high doses of APAP (Lee et al., 1996). The
CYP1A2-null mice, on the other hand, fail to demonstrate
that they are less sensitive to APAP toxicity, even within a
low dose range (Tonge et al., 1998). Furthermore, despite

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ACTIVATING PXR ENHANCED APAP TOXICITY

relatively lower basal levels of CYP1A2 and similar levels of

CYP2E1 in PXR-null mice livers compared to those in the
wild-type mice, the APAP toxicity was more severe in the
PXR-nulls, indicating that other P450 enzymes, probably
CYP3A11, contributed significantly to NAPQI formation.
The role of the CYP3A family in APAP metabolism has
been long speculated upon, and is confirmed to a certain
degree by studies using the so-called CYP3A-specific inhibitors; however, the lack of a CYP3A family gene knockout
model prohibits the direct investigation of this issue. Nevertheless, by using an indirect approach in the study here, a
PXR-null mouse model confirmed the critical role of PXRregulated CYP3A11 in APAP metabolism.
PXR also plays a critical role in regulating phase II xenobiotic metabolizing enzymes and transporters that are important to detoxifying xenobiotics. Although the role of GSTp in
NAPQI detoxification is not completely clear, it is reported to
be the major phase II enzyme responsible for detoxifying
NAPQI with APAP overdose. However, our study showed
that GSTp was induced by PCN in both wild-type and
PXR-null mice; this is probably due to overlapping activation
of other nuclear receptors, such as CAR that induces or stabilizes GSTp mRNA. Therefore the effect of GSTp by PCN
in both wild-type and PXR-null mice on APAP detoxification
is similar and can not count for the more severe APAPinduced hepatic injury in the PXR-null mice prior to PCN
pretreatment. Possible activation of other nuclear receptors
was also suggested by CYP1A2 expression, which was
induced to a moderate degree by PCN and inhibited by
APAP administration regardless of the genotypes or the combination with PCN, indicating that other nuclear receptors,
such as CAR that cross-talks with PXR (Zhang et al.,
2002), might be involved in regulating CYP1A2 expression
in these animals. The APAP metabolites are excreted out of
the liver into the circulation or bile by hepatic transporters,
such as Mrp3 and/or Mrp2 (Chen et al., 2003). The expression
of Mrp2 and Mrp3 is induced by PXR activation (Kast et al.,
2002; Teng et al., 2003). Thus, activation of PXR enhances
APAP-induced hepatic injury by induction of CYP3A
isoforms, but on the other hand, also aids in the detoxification of APAP overdose by induction of phase II enzymes and
transporters. However, data from this study showed
that bioactivation of APAP to its reactive intermediate metabolite, NAPQI, by CYP3A11 appeared to overcome the detoxification process mediated by phase II enzymes and
transporters, resulting in more severe APAP-induced hepatic
injury.
In summary, this study demonstrated that activation of PXR
dramatically enhanced APAP-induced hepatic injury mainly via
induction of CYP3A. This finding implies that chemicals that
modulate PXR activity will have a significant effect on the outcome following APAP administration, and it adds another layer
of complexity in understanding APAP metabolism and treatment for APAP overdose patients.

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