Free radical biology & medicine

Nitric oxide promotes strong cytotoxicity of phenolic compounds against Escherichia coli: the influence of antioxidant defenses.

PMID 14642385


The induction of mutagenic and cytotoxic effects by simple phenolics, including catechol (CAT), 3,4-dihydroxyphenylacetic acid (DOPAC), hydroquinone (HQ), and 2,5-dihydroxyphenylacetic (homogentisic) acid (HGA), appears to occur through an oxidative mechanism based on the ability of these compounds to undergo autoxidation, leading to quinone formation with the production of reactive oxygen species. This is supported by the detection of such adverse effects in plate assays using Escherichia coli tester strains deficient in the OxyR function, but not in OxyR(+) strains. The OxyR protein is a redox-sensitive regulator of genes encoding antioxidant enzymes including catalase and alkyl hydroperoxide reductase, which would eliminate hydrogen peroxide. Methyl-substituted phenolics such as 4-methylcatechol (MCAT) and methylhydroquinone (MHQ) produced, in addition to oxidative toxicity, marked cytotoxic effects against OxyR(+) cells, thus revealing a mechanism of toxicity not mediated by hydrogen peroxide that could involve quinones and quinone methides arising from MCAT and MHQ oxidation. Quinone compounds could also be responsible for the enhanced cytotoxicity of certain phenolics when combined with a nitric oxide (NO(*)) donor such as diethylamine/NO (DEA/NO). Phenolics scavenge NO(*) and, in turn, NO(*) oxidizes phenolics to form their quinone derivatives. In OxyR(+) cells, where the oxidative toxicity is inhibited, DEA/NO promoted exceptional increases in the cytotoxicity of CAT and 3,4-dihydroxycinnamic (caffeic) acid (CAF), which both exhibited very low oxidative cytotoxicity, as well as in that of MCAT, HQ, and MHQ. In contrast, DEA/NO failed to promote toxicity by DOPAC and HGA, probably due to their ability to undergo oxidative polymerization, leading to the formation of melanins. Spectroscopic studies demonstrated quinone generation from the oxidation of CAF, HQ, and MHQ by DEA/NO. The o-quinone derived from CAF was rather unstable and decomposed during its isolation. For the generation of toxic quinones, e.g., to be used as therapeutic agents producing antitumor or antibacterial effects, the isolation step could be avoided with the method proposed. It combines quinone precursors, i.e. phenolic compounds, with an oxidant such as NO(*).

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Methylhydroquinone, 99%
Methylhydroquinone, purum, ≥98.0% (HPLC)