title: Dose-dependent difference of nuclear receptors involved in murine liver hypertrophy by piperonyl butoxide.
abstract: Nuclear receptors play important roles in chemically induced liver hypertrophy in rodents. To clarify the involvement of constitutive androstane receptor (CAR) and other nuclear receptors in mouse liver hypertrophy induced by different doses of piperonyl butoxide (PBO), wild-type and CAR-knockout mice were administered PBO (200, 1,000, or 5,000 ppm) in the basal diet for 1 week. Increased liver weight and diffuse hepatocellular hypertrophy were observed at 5,000 ppm for both genotypes, accompanied by increased Cyp3a11 mRNA and CYP3A protein expression, suggesting that CAR-independent pathway, possibly pregnane X receptor (PXR), plays a major role in the induction of hypertrophy. Moreover, wild-type mice at 5,000 ppm showed enhanced hepatocellular hypertrophy and strong positive staining for CYP2B in the centrilobular area, suggesting the localized contribution of CAR. At 1,000 ppm, only wild-type mice showed liver weight increase and centrilobular hepatocellular hypertrophy concurrent with elevated Cyp2b10 mRNA expression and strong CYP2B staining, indicating that CAR was essential at 1,000 ppm. We concluded that high-dose PBO induced hypertrophy via CAR and another pathway, while lower dose of PBO induced a pathway mediated predominantly by CAR. The dose-responsiveness on liver hypertrophy is important for understanding the involvement of nuclear receptors.
authors.affiliation: Division of Pathology, National Institute of Health Sciences.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Sakamoto
authors.forename: Midori
authors.initials: M
authors.lastname: Yoshida
authors.forename: Kei
authors.initials: K
authors.lastname: Tamura
authors.forename: Miwa
authors.initials: M
authors.lastname: Takahashi
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kodama
authors.forename: Kaoru
authors.initials: K
authors.lastname: Inoue
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D006529:Hepatomegaly / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D006984:Hypertrophy; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008809:Mice, Inbred C3H; D009929:Organ Size / Q000187:drug effects; D010882:Piperonyl Butoxide / Q000009:adverse effects*; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044169:Receptors, Calcium-Sensing; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D011987:Receptors, Steroid / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D000072467:Cytochrome P450 Family 2; D008565:Membrane Proteins; D010882:Piperonyl Butoxide; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D044169:Receptors, Calcium-Sensing; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D011987:Receptors, Steroid; D013250:Steroid Hydroxylases; C577923:CASR protein, mouse; C101679:Cyp2b10 protein, mouse; C496508:Cyp3a11 protein, mouse