Role of the nuclear receptor pregnane X receptor in acetaminophen hepatotoxicity.
The pregnane X receptor (PXR) is a transcriptional regulator of xenobiotic metabolizing enzymes, including cytochrome P450 3A (CYP3A), and transporters. Pretreatment of mice and rats with inducers of CYP3A increases acetaminophen (APAP) hepatotoxicity. In untreated mice, the amount of hepatic CYP3A11 mRNA is 4-fold greater in PXR(-/-) mice compared to wild-type mice (Guo et al., 2003), a finding anticipated to increase APAP hepatotoxicity in PXR(-/-) mice. We investigated APAP hepatotoxicity in wild-type and PXR(-/-) mice in a C57BL/6 background, with APAP administered by gavage. Despite a 2.5-fold higher level of total hepatic CYP3A protein and a 3.6-fold higher level of CYP3A activity compared to wild-type mice, PXR(-/-) mice were less sensitive to APAP hepatotoxicity. Hepatic levels of CYP2E1 were identical in the two mouse lines, but hepatic CYP1A2 levels were 3-fold greater in wild-type mice compared to PXR(-/-) mice. Caffeine, an inhibitor of CYP1A2 activity and an enhancer of CYP3A activity, decreased APAP hepatotoxicity in wild-type mice. APAP uptake was 1.5-fold greater in wild-type mice compared to PXR(-/-) mice. No significant differences in the formation of APAP glucuronide and sulfate-conjugated metabolites were observed between wild-type and PXR(-/-) mice. Glutathione levels were similar in the two mouse lines and were transiently decreased to similar amounts after APAP administration. Our finding that APAP hepatotoxicity was decreased in PXR(-/-) mice indicates that PXR is an important modulator of APAP hepatotoxicity, through positive modulation of constitutive CYP1A2 expression and possibly through increased APAP absorption.
Wolf
Kristina K
KK
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire, USA.
Wood
Sheryl G
SG
Hunt
Jane A
JA
Walton-Strong
Brooke W
BW
Yasuda
Kazuto
K
Lan
Lubin
L
Duan
Su X
SX
Hao
Qin
Q
Wrighton
Steven A
SA
Jeffery
Elizabeth H
EH
Evans
Ronald M
RM
Szakacs
Juliana G
JG
von Moltke
Lisa L
LL
Greenblatt
David J
DJ
Court
Michael H
MH
Schuetz
Erin G
EG
Sinclair
Peter R
PR
Sinclair
Jacqueline F
JF
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D016227:Benzoquinones / Q000378:metabolism; D001692:Biological Transport; D002110:Caffeine / Q000494:pharmacology; D019388:Cytochrome P-450 CYP1A2 / Q000032:analysis; D019392:Cytochrome P-450 CYP2E1 / Q000032:analysis; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007097:Imines / Q000378:metabolism; D007408:Intestinal Absorption; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D011987:Receptors, Steroid / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D008565:Membrane Proteins
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000082:Acetaminophen; D016227:Benzoquinones; D002110:Caffeine; D019388:Cytochrome P-450 CYP1A2; D019392:Cytochrome P-450 CYP2E1; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione; D007097:Imines; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; C028473:N-acetyl-4-benzoquinoneimine; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins