Secondary nitroalkanes: Induction of DNA repair in rat hepatocytes, activation by aryl sulfotransferase and hepatocarcinogenicity of 2-nitrobutane and 3-nitropentane in male F344 rats

Fiala, Emerich S.; Sodum, Rama S.; Hussain, Nalband; Rivenson, Abraham; Dolan, Lisa

doi:10.1016/0300-483x(94)03004-l

Cited by 31 publications

(27 citation statements)

References 18 publications

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“…Of note, the 1‐NP used in this study was contaminated with 2.3% 2‐NP. The negative result in liver cells is consistent with the results of Fiala et al (1995) in which DNA repair was not induced in exposed rat hepatocytes (Fiala et al, 1995). Based on negative or marginal findings in two in vivo micronucleus assays (George et al, 1989; Kliesch & Adler, 1987) and in an in vitro chromosomal aberration study (Thompson, 1995), the WoE suggests that 1‐NP does not induce chromosomal effects.…”

Section: Resultssupporting

confidence: 92%

Hazard characterization of carcinogenicity, mutagenicity, and reproductive toxicity for short chain primary nitroalkanes

Garnick

Gillie

Kozal

et al. 2021

J of Applied Toxicology

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Nitroalkanes are organic aliphatic hydrocarbon compounds with a nitro moiety that are commonly used as solvents or intermediates to synthesize a variety of organic compounds due to their inherent reactivity. In June 2020, a harmonized classification and labeling (CLH) proposal was submitted to the European Chemicals Agency (ECHA) for the following harmonized carcinogenicity, mutagenicity, and reproductive toxicity (“CMR”) classifications for nitromethane (NM), nitroethane (NE), and 1‐nitropropane (1‐NP): NM Carc. 1B and Repr. 1B; NE Repr. 1B; and 1‐NP Repr. 2. In this assessment, a weight of evidence (WoE) evaluation of studies on animal carcinogenicity and reproductive and developmental toxicity, genotoxicity, and mode of action for these three nitroalkanes was performed to critically assess the relevance of the proposed CMR classifications. Overall, the WoE indicates that NM, NE, and 1‐NP are not carcinogenic, genotoxic, nor selective reproductive or developmental toxicants. Based on our analysis, classifying NM, NE, and 1‐NP as Category 2 reproductive toxicants is most appropriate. Furthermore, not classifying NE and 1‐NP with respect to their carcinogenicity is appropriate based on the available studies for this endpoint coupled with negative results in genotoxicity studies, metabolism data, and in silico predictions. We determined that the classification for NM of Carc. 1B is not appropriate, based on the fact that rat mammary and harderian tumors are likely not relevant to humans and lung and liver tumors reported in mice were equivocal in their dose–response and statistical significance.

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Section: Resultssupporting

confidence: 92%

Hazard characterization of carcinogenicity, mutagenicity, and reproductive toxicity for short chain primary nitroalkanes

Garnick

Gillie

Kozal

et al. 2021

J of Applied Toxicology

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“…Nitromethane, was however, not mutagenic in the Ames test, and gave a negative response in a mouse micronucleus assay, indicating a lack of genotoxic activity. This is consistent with reported findings that genotoxicity may be restricted to secondary alkyl nitro compounds (13). Degeneration of the olfactory epithelium, probably related to the route of exposure, was seen in the subchronic study.…”

Section: Resultssupporting

confidence: 81%

Prediction of rodent carcinogenicity using the DEREK system for 30 chemicals currently being tested by the National Toxicology Program. The DEREK Collaborative Group.

Marchant

1996

Environ Health Perspect

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“…Investigations on the carcinogenicity and genotoxicity of 2-NP eventually revealed that 2-NP is metabolically activated by specific liver enzymes [161][162][163]. Recent evidence proved that hepatic SULT activity is required for the metabolic activation of 2-NP and its anionic form, propane 2nitronate (P2N), and also other secondary nitroalkanes such as nitrocyclohexane and nitrocyclopentane, to reactive species that are capable of inducing genotoxic effects [164][165][166][167]. For example, Sodum et al determined an aminated-DNA adduct, 8-aminoguanine, and postulated that aryl-SULT-mediated sulfation might have a role in the formation of this adduct [168].…”

Section: Sult-mediated Bioactivation Of 2-nitropropane and Other Secomentioning

confidence: 99%

“…10), wherein an unsubstituted nitrenium ion (NH 2 + ) could possibly be formed and aminate proteins and nucleic acids [165,168,169]. They also showed that in vitro sulfation of 2-NP catalyzed by aryl-SULT resulted in 8-aminoguanine and 8-oxoguanine adducts, as well as an unidentified modified guanosine nucleoside [165,167,168]. They subsequently characterized the previously unidentified modified nucleoside as 2-hydrazinohypoxanthine (N 2aminoguanine) [170].…”

Section: Sult-mediated Bioactivation Of 2-nitropropane and Other Secomentioning

confidence: 99%

Current Status of the Cytosolic Sulfotransferases in the Metabolic Activation of Promutagens and Procarcinogens

Banoğlu

2000

CDM

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Cytosolic sulfotransferases (SULT) catalyze the sulfation of structurally diverse drugs, endogenous compounds and xenobiotics. These reactions involve the transfer of a sulfuryl group from 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to the hydroxyl/amino groups of acceptor molecules. Although sulfate conjugation is generally considered as a detoxication pathway producing more water-soluble and often less toxic metabolites, sulfation of certain classes of compounds produce sufficiently electrophilic metabolites that can covalently bind to cellular macromolecules, DNA and RNA. The important roles of electrophilic sulfate ester metabolites in the metabolic activation, mutagenicity and ultimate carcinogenicity of many xenobiotics have been considerably elucidated. Examples include the class of hydroxymethyl polycyclic aromatic hydrocarbons, allylic alcohols, N-hydroxy derivatives of carcinogenic arylamines and heterocyclic amines. Results obtained by many scientists during the last two decade correlate with a hypothesis that electrophilic sulfate esters may be the major ultimate carcinogenic forms of many, if not most, procarcinogens derived from benzylic/allylic alcohols and hydroxy arylamines. Careful analysis of these results suggest that the activities of human hydroxysteroid sulfotransferase (hHST), and a related form in rat liver, rat hydroxysteroid sulfotransferase a (STa), as well as aryl sulfotransferases both from rat and human liver, account for a substantial portion of the activation of benzylic/allylic alcohols in these species. Moreover, aryl sulfotransferases have also been indicated as the responsible SULT family in the bioactivation of hydroxy arylamines in the liver of different species including human. Molecular cloning of the individual sulfotransferases and expression of these individual forms in heterologous expression systems have allowed us to better understand the role of SULTs in the bioactivation of different procarcinogens and the form of sulfotransferase involved in their bioactivation. Additional structure-activity studies with homogeneous forms of rat liver STa and AST IV have also yielded comparative insight into some of the parameters important in recognition of substrates and inhibitors by these enzymes.

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Secondary nitroalkanes: Induction of DNA repair in rat hepatocytes, activation by aryl sulfotransferase and hepatocarcinogenicity of 2-nitrobutane and 3-nitropentane in male F344 rats

Cited by 31 publications

References 18 publications

Hazard characterization of carcinogenicity, mutagenicity, and reproductive toxicity for short chain primary nitroalkanes

Hazard characterization of carcinogenicity, mutagenicity, and reproductive toxicity for short chain primary nitroalkanes

Prediction of rodent carcinogenicity using the DEREK system for 30 chemicals currently being tested by the National Toxicology Program. The DEREK Collaborative Group.

Current Status of the Cytosolic Sulfotransferases in the Metabolic Activation of Promutagens and Procarcinogens

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