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Cancer Sci. 2009 Mar;100(3):382-8. doi: 10.1111/j.1349-7006.2008.01050.x. Epub 2008 Dec 15.

V-PROLI/NO, a nitric oxide donor prodrug, protects liver cells from arsenic-induced toxicity.

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  • 1Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.


Inorganic arsenic shows great promise in human cancer chemotherapy, although hepatotoxicity is a major limiting side-effect. O(2)-Vinyl 1-[2-(Carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (V-PROLI/NO) [Correction added after publication 19 December 2008: 1-[2-(Carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (V-PROLI/NO) was corrected to O(2)-Vinyl 1-[2-(Carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (V-PROLI/NO)] is a nitric oxide (NO) donor prodrug that is metabolized by liver cytochromes P450 to release NO. Other NO-releasing agents have been shown to mitigate arsenic toxicity. Thus, the effects of V-PROLI/NO pretreatment on the toxicity of inorganic arsenic (as NaAsO(2)) were studied in vitro in a human liver (HepG2) cell line. HepG2 cells acted upon the prodrug to release NO, as assessed by nitrite levels, in a dose- and time-dependent fashion to maximal levels of 57-fold above control levels. In cells pretreated with V-PROLI/NO (200 microM, 24 h) then exposed to arsenic for an additional 24 h, arsenic was much less toxic (LC(50) = 151.9 +/- 5.9 microM) than in control cells (LC(50) = 90.5 +/- 6.5 microM) and the reduced cytolethality was directly related to the level of NO produced. V-PROLI/NO also increased CYP2E1 transcriptional expression in a dose-dependent manner and CYP2E1 expression was directly related to the level of NO produced and the reduction in arsenic cytotoxicity. V-PROLI/NO pretreatment markedly reduced arsenic-induced apoptosis as measured by DNA fragmentation. Pretreatment with V-PROLI/NO suppressed phosphorylation of JNK1/2 after arsenic exposure. Arsenic increased metallothionein, a metal-binding protein important in arsenic tolerance, and V-PROLI/NO pretreatment caused additional increases in metallothionein levels. Thus, the prodrug, V-PROLI/NO, protects against arsenic toxicity in cultured human liver cells, reducing cytolethality, apoptosis and dysregulation of mitogen-activated protein kinases, through generation of NO formed after metabolism by liver cell enzymes, possibly including CYP2E1.

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