Functional role of phospholipase D (PLD) in di(2-ethylhexyl) phthalate-induced hepatotoxicity in Sprague-Dawley rats.
Phospholipase D (PLD) is an enzyme that catalyzes the hydrolysis of phosphatidyl choline (PC) to generate phosphatidic acid (PA) and choline. PLD is believed to play an important role in cell proliferation, survival signaling, cell transformation, and tumor progression. However, it remains to be determined whether enhanced expression of PLD in liver is sufficient to induce hepatotoxicity. The aim of this study was to investigate the possible role of PLD in di(2-ethylhexyl) phthalate (DEHP)-induced hepatotoxicity in Sprague-Dawley rats. The phthalate, DEHP (500 mg/kg/d), was administered orally, daily to prepubertal rats (4 wk of age, weighing approximately 70-90 g) for 1, 7, or 28 d. In this study, protein expression levels of PLD1/2, peroxisome proliferator-activated receptor (PPAR), and cytochrome P-450 (CYP) were determined by Western blot analysis using specific antibodies. Liver weight was significantly increased in the DEHP treatment groups. Immunohistochemical analysis demonstrated that DEHP produced strong staining of proliferating cell nuclear antigen (PCNA) at 28 d of exposure, suggestive of hepatocyte proliferation. A significant rise in PLD1/2 expression was observed in liver of DEHP-exposed rats after 7 d. Further, PPARα, constitutive androstane receptor (CAR), pregnane X receptor (PXR), and CYP2B1 protein expression levels were markedly elevated in DEHP-treated groups. Our results suggest that DEHP significantly enhanced the expression of PLD, which may be correlated with PPARα-induced hepatotoxicity through a complex interaction with nuclear receptors including CAR and PXR.
Kim
Na Young
NY
Laboratory of Molecular Toxicology, College of Pharmacy, Pusan National University, Busan, South Korea.
Kim
Tae Hyung
TH
Lee
Ena
E
Patra
Nabanita
N
Lee
Jaewon
J
Shin
Mi Ok
MO
Kwack
Seung Jun
SJ
Park
Kui Lea
KL
Han
Soon Young
SY
Kang
Tae Seok
TS
Kim
Seung Hee
SH
Lee
Byung Mu
BM
Kim
Hyung Sik
HS
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D010739:Phospholipase D / Q000378:metabolism*; D010968:Plasticizers / Q000633:toxicity*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013737:Testis / Q000187:drug effects / Q000473:pathology
D015415:Biomarkers; D047492:Peroxisome Proliferator-Activated Receptors; D010968:Plasticizers; D018809:Proliferating Cell Nuclear Antigen; D003577:Cytochrome P-450 Enzyme System; D004051:Diethylhexyl Phthalate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D010739:Phospholipase D; C106801:phospholipase D1