Nitric oxide donor, V-PROLI/NO, provides protection against arsenical induced toxicity in rat liver cells: Requirement for Cyp1a1

Abstract

Arsenic is a cancer chemotherapeutic but hepatotoxicity can be a limiting side effect. O2-Vinyl 1-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (V-PROLI/NO) is a nitric oxide (NO) donor prodrug and metabolized by liver cytochromes P450 (CYP450) to release NO. The effects of V-PROLI/NO pretreatment on the toxicity of arsenic (as NaAsO2) were studied in a rat liver cell line (TRL 1215). The cells acted upon the prodrug to release NO, as assessed by nitrite levels, in a time-dependent fashion to maximal levels of 8-fold above basal levels. Pretreatment with V-PROLI/NO markedly reduced arsenic cytolethality which was directly related to the level of NO produced by V-PROLI/NO treatment. Cyp1a1 expression was directly related to the level of NO production and to reduced arsenic cytotoxicity. V-PROLI/NO pretreatment markedly reduced arsenic-induced apoptosis and suppressed phosphorylation of JNK1/2. V-PROLI/NO pretreatment facilitated additional increases in arsenic-induced metallothionein, a metal-binding protein important in arsenic tolerance. Thus, V-PROLI/NO protects against arsenic toxicity in rat liver cells, reducing cytolethality, apoptosis and dysregulation of MAPKs, through generation of NO formed after metabolism by liver cell enzymes, possibly including Cyp1a1. CYP450 required for NO production from V-PROLI/NO treatment in the rat and human appears to differ as we have previously studied the ability of V-PROLI/NO to prevent arsenic toxicity in human liver cells where it reduced toxicity apparently through a CYP2E1-mediated metabolic mechanism. None-the-less, it appears that both rat and human liver cells act upon V-PROLI/NO via a CYP450-related mechanism to produce NO and subsequently reduce arsenic toxicity.

Generation of Reactive Oxygen Species by Polyenylpyrroles Derivatives Causes DNA Damage Leading to G2/M Arrest and Apoptosis in Human Oral Squamous Cell Carcinoma Cells

“…It has been suggested that cytochrome P450 1A1 promotes DNA damage and G2/M arrest in benzo[a]pyrene-stimulated breast carcinoma MCF-7 cells [37]. In contrast, cytochrome P450 1A1 is able to detoxify toxins, for examples, it plays a protective role in benzo[a]pyrene-induced oral cancer in mice [38] and in arsenic toxicity in rat liver cells by reducing apoptosis [39]. Cytochrome P450 1A1 polymorphism on exon 7 has also be shown to be capable of modifying the susceptibility to oral cancer among Asians [40].…”

In Vivo and In Vitro Arsenic Exposition Induces Oxidative Stress in Anterior Pituitary Gland

“…47,48 Heme oxygenase-1 is a well-known biomarker of iAs-induced oxidative stress and is thought to be involved in toxic metalloid adaptation. 49 Similarly, MT-1 is a metal-binding protein with high sulfhydryl content that defends against metal-induced oxidative cell injury. 50 Arsenic induces MT-1 expression both in vitro and in vivo, 51,52 possibly by binding to the MT-1 promoter.…”