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: Jie Liu, Yu-Ying He, Colin F Chignell, James Clark, Page Myers, Joseph E Saavedra, Michael P Waalkes
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 70 Issue 1 Pg. 144-51 (Jul 01 2005) ISSN: 0006-2952 [Print] England
• PMID: 15913567 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Nitric Oxide Donors
• O(2)-vinyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate
• Pyrrolidines
• 1-Naphthylisothiocyanate

Topics

• 1-Naphthylisothiocyanate (toxicity)
• Animals
• Cholestasis, Intrahepatic (prevention & control)
• Gene Expression Profiling
• Liver (drug effects, metabolism)
• Male
• Mice
• Nitric Oxide Donors (pharmacology)
• Pyrrolidines (pharmacology)