p-Aminophenol induced DNA damage and cytotoxicity enhanced by autoxidation

doi:10.1016/0024-3205(85)90454-0

Life Sciences

Volume 36, Issue 21, 27 May 1985, Pages 2039-2046

https://doi.org/10.1016/0024-3205(85)90454-0 Get rights and content

Abstract

p-Aminophenol inhibits DNA synthesis and alters the structure of DNA. A decrease in sedimentation of nucleoids from cells treated with p-aminophenol was observed and this decrease in sedimentation was considerably less when cells were incubated with p-aminophenol in an atmosphere of nitrogen or at lower pH values. This compound was also shown to be cytotoxic to cells in culture. These results demonstrate that conditions retarding the autoxidation of p-aminophenol lead to reduced effects on DNA structure and a lesser cytotoxic effect.

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Cited by (6)

Mutagenicity of p-aminophenol in E. coli WP2uvrA/pKM101 and its relevance to oxidative DNA damage
1998, Mutation Research - Genetic Toxicology and Environmental Mutagenesis
It was recently reported that p-aminophenol (p-AP) induces DNA cleavage in mouse lymphoma cells, CHO cells and human lymphoblastoid cells. The mutagenicity of p-AP has not, however, been detected by reverse mutation assays. The purpose of this study was to assess the mutagenicity of p-AP by reverse mutation assay using Escherichia coli WP2uvrA/pKM101, which has a spectrum for detecting mutations different from those of other strains in the family with an AT base pair at the mutation site and has higher sensitivity to certain oxidative mutagens as compared to other strains. We found that p-AP was mutagenic to E. coli WP2uvrA/pKM101. The mutagenic activity of this compound was suppressed with the addition of dimethylsulfoxide or catalase, suggesting the involvement of active oxygen species in the mutagenic process induced by p-AP. To further elucidate the underlying mechanism, we used isolated DNA for the following experiments. It was revealed, by gel electrophoretic analysis, that p-AP induced DNA cleavage in the presence of Fe(III). However, p-AP alone did not induce this cleavage. Formation of 8-oxo-7,8-dihydro-2′-deoxyguanosine by p-AP in calf thymus DNA was also detected in the presence of Fe(III) by HPLC with an electrochemical detector. ESR-spin trapping experiments using DMPO detected the production of hydroxyl radical (^⋅OH) in the solution of p-AP with Fe(III). Both p-AP mediated DNA damages and ^⋅OH production by p-AP in the presence of Fe(III) were completely inhibited by ^⋅OH scavengers (ethanol, mannitol, sodium formate, dimethylsulfoxide) and catalase. These results suggest that ^⋅OH derived from the reaction between H₂O₂ and Fe(III) (Fenton reaction) participates in the oxidative DNA damage. Accordingly, the same mechanism might be working in E. coli WP2uvrA/pKM101 during induction of the mutation by p-AP.
Lack of correlation between para-aminophenol toxicity in vivo and in vitro in female Sprague-Dawley rats
1996, Fundamental and Applied Toxicology
The present study was designed to test the hypothesis thatpara-aminophenol (PAP) nephrotoxicity is due to autooxidation. We compared renal functional responses following PAP administration to female Sprague–Dawley rats and following incubation of renal proximal tubules with PAP. The concentrations of PAP selected forin vitroincubations produced cytotoxicity (for example, a decrease in oxygen consumption or adenine nucleotide concentration) in rat renal epithelial cells or rabbit proximal tubule suspensions. In rats, PAP (300 mg/kg ip) caused proximal tubular necrosis within 24 hr. Changes in renal function 24 hr following PAP administration included increased kidney weight and blood urea nitrogen concentration and decreased renal glutathione (GSH) content and adenine nucleotide concentrations. PAP did not cause hepatic damage. Within 2–4 hr following PAP administration, renal GSH content and adenine nucleotide concentrations were significantly decreased. In renal cortical slices prepared from PAP-treated rats, oxygen consumption and accumulation of organic ions (para-aminohippurate and tetraethylammonium) were significantly decreased compared with renal cortical slices prepared from control rats. In liver, GSH content was significantly decreased from 1 to 4 hr following PAP administration. In contrast to the effects of PAPin vivo,renal proximal tubules showed little evidence of injury when incubated with 0.1 or 0.5 mMPAP for up to 4 hr in the presence or absence of amino acids in the incubation medium. When tubules were incubated with 1 mMPAP for 4 hr in the presence of amino acids, GSH content, AMP concentration, and TEA uptake were significantly decreased. When amino acids were removed from the incubation medium, 1 mMPAP caused decreases in oxygen consumption and ATP concentration after 4 hr of incubation. Functional changes observed during incubation with PAPin vitrowere not consistent with functional changes observedin vivo.The discrepancy between PAP toxicityin vivoandin vitrosuggests that autooxidation is unlikely to be responsible for PAP nephrotoxicity and that nephrotoxicityin vivois primarily mediated by extrarenal bioactivation. Further, depletion of hepatic GSH content prior to changes in renal function suggests that PAP or a PAP metabolite may conjugate with hepatic GSH. These observations suggest that PAP nephrotoxicity may be mediated by PAP–GSH conjugates rather than autooxidation of PAP in the kidney.
Effect of N-hydroxyparacetamol on cell cycle progression
1986, Biochemical Pharmacology
N-hydroxparacetamol treatment of rat kidney cells gave rise to a dose-dependent decrease in DNA synthesis. A concentration of 1.0 mM N-hydroxyparacetamol at pH 7.2 decreased the level of DNA synthesis to 13.0 ± 2.3% of the control value after 1 hr incubation. This compound also caused a perturbation of cell cycle progression. A concentration of 0.44 mM N-hydroxyparacetamol induced G1/S and S phase blocks. These delays became evident at approximately 12 hr after treatment and persisted until about 15 hr when cells started to recover. It seems unlikely that N-hydroxyparacetamol inhibits DNA synthesis and perturbs cycle progression through alterations to DNA structure as such, since this compound failed to alter the migration pattern of naked plasmid DNA.
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p-Aminophenol induced DNA damage and cytotoxicity enhanced by autoxidation

Abstract

Biochem. Pharmacol.

Chem. Biol. Interact.

J. Biol. Chem.

Life Sci.

Biochem. Pharmacol.

Mut. Res.

Clin. Sci. Molec. Med.

Brit. Med. J.

Aust. N.Z. J. Med.

Xenobiotica

Xenobiotica