title: 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. 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 and metabolized by liver cytochromes P450 (CYP450) to release NO. The effects of V-PROLI/NO pretreatment on the toxicity of arsenic (as NaAsO(2)) 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.
authors.affiliation: National Toxicology Program, National Institute of Environmental Health Sciences and Laboratory of Comparative Carcinogenesis, National Cancer Institute, 111 Alexander Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Qu
authors.forename: Lida
authors.initials: L
authors.lastname: Cheng
authors.forename: Anna L
authors.initials: AL
authors.lastname: Dill
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Saavedra
authors.forename: Sam Y
authors.initials: SY
authors.lastname: Hong
authors.forename: Larry K
authors.initials: LK
authors.lastname: Keefer
authors.forename: Michael P
authors.initials: MP
authors.lastname: Waalkes
mesh_terms: D000818:Animals; D017209:Apoptosis; D001151:Arsenic / Q000633:toxicity*; D002460:Cell Line; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D048688:MAP Kinase Kinase 7 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D014226:Triazenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D020030:Nitric Oxide Donors; C560906:O2-vinyl 1-(2-(carboxylato)pyrrolidin-1-yl)diazen-1-ium-1,2-diolate; D011355:Prodrugs; D011759:Pyrrolidines; D014226:Triazenes; D009569:Nitric Oxide; D019363:Cytochrome P-450 CYP1A1; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; D001151:Arsenic