Abstract
4-Nitroquinoline 1-oxide (4NQO) is used as a positive control in various genotoxicity assays because of its known mutagenic and carcinogenic properties. The chemical is converted into 4-hydroxyaminoquinoline 1-oxide and gives rise to three main DNA adducts, N-(deoxyguanosin-8-yl)-4AQO, 3-(desoxyguanosin-N 2-yl)-4AQO and 3-(deoxyadenosin-N 6-yl)-4AQO. This study was designed to assess the shape of the dose–response curve at low concentrations of 4NQO in three human lymphoblastoid cell lines, MCL-5, AHH-1 and TK6 as well as the mouse lymphoma L5178Y cell line in vitro. Chromosomal damage was investigated using the in vitro micronucleus assay, while further gene mutation and DNA damage studies were carried out using the hypoxanthine–guanine phosphoribosyltransferase forward mutation and comet assays. 4NQO showed little to no significant increases in micronucleus induction in the human lymphoblastoid cell lines, even up to 55±5% toxicity. A dose–response relationship could only be observed in the mouse lymphoma cell line L5178Y after 4NQO treatment, even at concentrations with no reduction in cell viability. Further significant increases in gene mutation and DNA damage induction were observed. Hence, 4NQO is a more effective point mutagen than clastogen, and its suitability as a positive control for genotoxicity testing has to be evaluated for every individual assay.
Highlights
Genetic toxicology involves the assessment of a substance’s ability to induce DNA damage, which is an essential consideration for human health risk assessment because DNA damage is an underlying cause of mutations that have the potential to initiate carcinogenesis
This study investigated the DNA damage induction by 4-Nitroquinoline 1-oxide (4NQO) at a low concentration range. 4NQO’s carcinogenic action is believed to be initiated by the enzymatic reduction of its nitro group [15,31]
The reduction product 4-hydroxyaminoquinoline 1-oxide (4HAQO) of 4NQO reacts with DNA to form stable monoadducts with purine bases, which are considered to be responsible for its mutagenicity and genotoxicity [15]
Summary
Genetic toxicology involves the assessment of a substance’s ability to induce DNA damage, which is an essential consideration for human health risk assessment because DNA damage is an underlying cause of mutations that have the potential to initiate carcinogenesis. It is essential to investigate and understand the biological significance of genotoxic effects of chemicals at the low-dose exposure range to improve human health risk assessment and to establish if DNA reactive compounds follow linear or non-linear dose–response relationships. High concentrations of genotoxins were used in in vitro testing to ensure that DNA damaging effects were identified and because of the assumption that genotoxins follow a linear relationship that was extrapolated back to the low-dose region [1]. Genotoxicants can interact with DNA by various mechanisms, such as direct interaction of the compound with DNA, interaction of the compound with cellular components that cause indirect DNA damage and DNA damage can be induced through activation of the
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