title: Limited protective role of V-PYRRO/NO against cholestasis produced by alpha-naphthylisothiocyanate in mice.
abstract: O(2)-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO) is a liver-selective nitric oxide donor that has been shown to protect against hepatotoxic effects of endotoxin, acetaminophen and cadmium. This study examined the effects of V-PYRRO/NO on alpha-naphthylisothiocyanate (ANIT)-induced hepatotoxicity in mice. Mice were given V-PYRRO/NO via osmotic pumps (5.4mg/ml; 0.5 microl/h) starting 24h before receiving a hepatotoxic dose of ANIT (150mg/kg in olive oil, i.g.), and continuing for additional 48h (3-day pumps). V-PYRRO/NO administration partially ameliorated ANIT-induced hepatotoxicity, as evidenced by reduced serum alanine aminotransferase and alkaline phosphatase, markers of liver cell death, and by improved liver pathology. However, V-PYRRO/NO had no effect on ANIT-induced cholestasis, as ANIT-increased serum bilirubin levels and gamma-glutamyl transpeptidase activity were not ameliorated. Microarray and real time RT-PCR analysis revealed that ANIT intoxication altered expression of various genes, including genes encoding metabolic enzymes, transporter proteins, acute phase proteins, inflammation- and, apoptosis-related genes, as well as other genes related to liver injury. V-PYRRO/NO treatment attenuated ANIT-induced elevations in certain inflammation- and apoptosis-related genes, but had no effect on ANIT-induced disturbance on the expression of genes related to metabolism, transport, and acute phase proteins. Thus, the liver-selective NO donor, V-PYRRO/NO, was partially protective against ANIT-induced liver injury, without affecting ANIT-induced cholestasis and cholestasis-related gene expression.
authors.affiliation: Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, NCI at NIEHS, Mail Drop F0-09, 111 Alexander Drive, Research Triangle Park, NC 27709, USA. liu6@niehs.nih.gov <liu6@niehs.nih.gov>
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Yu-Ying
authors.initials: YY
authors.lastname: He
authors.forename: Colin F
authors.initials: CF
authors.lastname: Chignell
authors.forename: James
authors.initials: J
authors.lastname: Clark
authors.forename: Page
authors.initials: P
authors.lastname: Myers
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Saavedra
authors.forename: Michael P
authors.initials: MP
authors.lastname: Waalkes
mesh_terms: D015058:1-Naphthylisothiocyanate / Q000633:toxicity*; D000818:Animals; D002780:Cholestasis, Intrahepatic / Q000517:prevention & control*; D020869:Gene Expression Profiling; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*
chemical_list: D020030:Nitric Oxide Donors; C107010:O(2)-vinyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate; D011759:Pyrrolidines; D015058:1-Naphthylisothiocyanate