Disease relevance of NSC 5369

• The acute toxicity of 2-nitropropane has not been widely appreciated despite previous reports of death due to hepatic failure after exposure to the compound in confined spaces [1].
• Here we report the first crystal structure of 2-nitropropane dioxygenase from Pseudomonas aeruginosa in two forms: a binary complex with FMN and a ternary complex with both FMN and 2-nitropropane [2].
• Both the mutagenicity in Salmonella typhimurium (strains TA100 and TA102) and the rate of tautomerisation to the nitronate was lower with 2-deutero-2-nitropropane than with non-deuterated 2-nitropropane [3].
• Propane 2-nitronate therefore appears to be pivotal in the causation of the genetic toxicity of 2-nitropropane [3].
• We have investigated the importance of nitronate formation from 2-nitropropane (2-NP) for the oxidative metabolism and the genotoxicity of 2-NP in 2sFou rat hepatoma cells [4].

High impact information on NSC 5369

• Fulminant hepatic failure after occupational exposure to 2-nitropropane [1].
• Two construction workers became ill after applying an epoxy resin coating containing 2-nitropropane in the confined space of an underground concrete vault [1].
• 2-Nitropropane dioxygenases from Neurospora crassa and Williopsis mrakii (Hansenula mrakii), members of one family of the nitroalkane-oxidizing enzymes, contain FMN and FAD, respectively [2].
• Wild-type (MT(+/+)) and MT-null (MT(-/-)) mice were treated with either saline or zinc and exposed to two types of oxidative stress: gamma-irradiation or 2-nitropropane [5].
• We then determined (1) the ability of liver microsomes to denitrify 2-nitropropane, (2) effects on 2-nitropropane-induced liver DNA and RNA modifications and (3) amount of nitrate excreted in rat urine following administration of the carcinogen [6].

Chemical compound and disease context of NSC 5369

• Nitronates of the secondary nitroalkanes 2-nitropropane, 2-nitrobutane, 3-nitropentane, and nitrocyclopentane were significantly mutagenic in Salmonella strains TA100 and TA102 at 10-80 mumoles/plate, but the parent compounds were mutagenic at only a single dose level or were not mutagenic at all in the same dose range [7].
• Genotoxicity of 2-nitropropane and 1-nitropropane in Salmonella typhimurium and human lymphocytes [8].
• Male rats were given 2% green tea as their drinking water for 2 wk before a single ip injection of the carcinogen 2-nitropropane (2NP) (100 mg/kg body weight) and liver nuclear 8-hydroxydeoxyguanosine (8-OHdG) levels and hepatotoxicity parameters were determined 6 or 15 hr thereafter [9].

Biological context of NSC 5369

• 2-Nitropropane induces DNA repair synthesis in rat hepatocytes in vitro and in vivo [10].
• It is proposed that nonenzymatic formation of NO2.radicals after enzymatic oxidation of propane-2-nitronate to the corresponding secondary alkyl radical accounts for the induction of DNA damage observed after exposure of rats to 2-nitropropane [11].
• To submit this postulate to further test, we examined liver proteins of rats treated with 2-nitropropane, other carcinogenic secondary nitroalkanes, or the related rat liver tumorigen acetoxime for the presence of 3-aminotyrosine, the expected product of tyrosine amination [12].
• Chromosome analyses were carried out in human lymphocytes treated in vitro with 2-nitropropane (2-NP) in the presence and absence of the mammalian metabolic activation system, S9 mix [13].
• Analysis of cytogenetic effect in human lymphocytes induced by metabolically activated 2-nitropropane [13].

Anatomical context of NSC 5369

• 2-Nitropropane-induced DNA damage in rat bone marrow [14].
• Hepatic microsomes from 5 strains of untreated mice were tested for the ability to enzymatically cleave the nitro group from 2-nitropropane (2NP) [15].
• Catalysis of nitro-aci tautomerism of the genotoxicant 2-nitropropane by cytosol from rodent and human liver [16].
• The metabolic pathways leading to genotoxicity of nitropropanes in mammalian cells were investigated by measuring the effects of 2-nitropropane (2-NP) and 1-nitropropane (1-NP) on various cell lines characterized for their expression of cytochrome P450-dependent mono-oxygenases [17].
• Intraperitoneal injection (50 mg/kg) of 2-nitropropane (2-NP) induced lipid accumulation, centrilobular necrosis, degranulation of rough endoplasmic reticulum, proliferation of smooth endoplasmic reticulum and mitochondrial abnormalities in rat liver 24 h after exposure [18].

Associations of NSC 5369 with other chemical compounds

• The genotoxicity of 2-nitropropane (2-NP) and 1-nitropropane (1-NP) was investigated by measuring the induction of DNA repair synthesis in rat liver cells in vitro and in vivo [10].
• Acetoxime (ACO) and 2-nitropropane (2-NP), both industrially important chemicals and known hepatocarcinogens in rats, induced increased levels of 8-hydroxy-guanine in liver DNA and RNA of male Sprague-Dawley and F344 rats after either oral or i.p. administration [19].
• 1-Nitropropane (1-NP), 2-nitropropane (2-NP), 1-azoxypropane (1-AP) and 2-azoxypropane (2-AP), were assayed for carcinogenicity by gavage in male Sprague-Dawley rats [20].
• Purification, characterization, and mechanism of a flavin mononucleotide-dependent 2-nitropropane dioxygenase from Neurospora crassa [21].
• In addition, we have demonstrated the in vitro DNA-modifying activity of 2-nitropropane, and present evidence to suggest that genetic activity of this nitroalkane may not be dependent on the enzymic reduction of the nitro function to the corresponding hydroxylamine [22].

Gene context of NSC 5369

• Activation of the liver carcinogen 2-nitropropane by aryl sulfotransferase [23].
• Cytochrome P-450-mediated denitrification of 2-nitropropane in mouse liver microsomes [24].
• Enzymatic denitrification of 2-nitropropane (2NP) was investigated in an NADPH-dependent hepatic microsomal system from male CD1 mice [24].

Analytical, diagnostic and therapeutic context of NSC 5369

• Size exclusion chromatography, heat denaturation, and mass spectroscopic analyses showed that 2-nitropropane dioxygenase is a homodimer of 80 kDa, containing a mole of non-covalently bound FMN per mole of subunit, and is devoid of iron [25].
• 2-Nitropropane (2-NP), an important industrial chemical and a hepatocarcinogen in rats, had previously been found to produce several modifications of nucleosides in rat liver RNA and DNA that are discernible using HPLC with electrochemical detection [26].
• By means of 2-nitropropane we have shown correspondence between the increases in 8-oxodG in target organs and the urinary excretion of 8-oxodG and between 8-oxodG formation and the comet assay in bone marrow as well potent preventive effects of extracts of Brussels sprouts [27].
• Protective effects of green tea on hepatotoxicity, oxidative DNA damage and cell proliferation in the rat liver induced by repeated oral administration of 2-nitropropane [28].
• New experimental results are reported on molecular interactions in the n-ethylamines and 2-nitropropane (2-NP)/n-ethylamine mixtures studied by Raman spectroscopy under pressure in a diamond anvil cell (0-50 GPa) and, at ambient pressure, by infrared spectroscopy [29].

References