Open AccessGeneration of Hydroxyl Radicals by the Antiviral Compound Phosphonoformic Acid (Foscarnet)
Author(s) -
Lindqvist Christer,
Nordström Tommy
Publication year - 2001
Publication title -
pharmacology & toxicology
Language(s) - English
Resource type - Journals
eISSN - 1600-0773
pISSN - 0901-9928
DOI - 10.1111/j.1600-0773.2001.890108.x
Subject(s) - chemistry , radical , hydroxyl radical , foscarnet , ascorbic acid , hydrogen peroxide , deoxyribose , photochemistry , medicinal chemistry , organic chemistry , biochemistry , human cytomegalovirus , gene , dna , food science , ganciclovir
Abstract: Phosphonoformic acid (foscarnet) is an antiviral agent that is used to treat severe cytomegalovirus infections in AIDS patients. We demonstrate by using the ferrous iron indicator Ferrozine and ascorbic acid (vitamin C) that foscarnet can chelate ferric iron and form a redox‐active iron complex. By using the hydroxyl radical indicator coumarin‐3‐carboxylic acid we found that the foscarnet‐Fe 3 complex formed can readily catalyze hydroxyl radical ( ˙ OH) generation by the Fenton reaction: (Fe 2+ + H 2 O 2 →Fe 3+ + ˙ OH + − OH) if hydrogen peroxide and ascorbic acid are present. Hydroxylation of coumarin‐3‐carboxylic acid could be blocked by addition of known hydroxyl radical scavengers such as mannitol, sucrose, glucose and dimethyl sulfoxide. Moreover, by using a DNA nicking assay, we found that foscarnet catalyzed hydroxyl radicals can induce single strand brakes in DNA. The potency of the hydroxyl radicals formed to induce damage could also be demonstrated in a phosphate‐free buffer where the hydroxyl radicals formed attacked and liberated phosphate from the foscarnet molecule. Our results indicate that foscarnet catalyzed hydroxyl radical formation might take place during conditions where a peroxide generating system(s), vitamin C and transitions metals are present.