title: Formation of DNA-damaging N-nitroso compounds from the interaction of calcium-channel blockers with nitrite.
abstract: A large number of drugs have been shown to react with nitrite to give genotoxic-carcinogenic N-nitroso compounds (NOC). However, the majority of drugs remain to be examined in this respect, among which calcium-channel blockers, all theoretically nitrosatable and widely used in the therapy of hypertension and other cardiovascular diseases. In this preliminary investigation, seven calcium-channel blockers have been examined either for their in vitro nitrosation according to the procedure recommended by the WHO, or for occurrence of liver DNA fragmentation, as detected by the Comet assay, in rats given by gavage 1/2 LD50 of the drug and 80 mg/kg of sodium nitrite. After 6h incubation the yields of NOC formed in vitro from nicardipine, nifedipine, nimodipine and nitrendipine ranged from 37 to 45% of the theoretical one, whereas the yields of NOC formed from diltiazem, gallopamil and verapamil ranged from 2 to 5%. In vivo, as compared with the effect of the same dose of the drug alone, a significant increase of both tail length and tail moment, indicative of an increased frequency of DNA single-strand breaks and alkali-labile sites, was produced in rat liver DNA by the administration with nitrite of gallopamil, nifedipine, nimodipine and nitrendipine, the ratio [tail length of drug+NaNO(2)/tail length of drug alone] being 3.2 for nimodipine, 3.1 for gallopamil 2.2 for nifedipine, and 2.1 for nitrendipine. Even if present, the increase in the degree of DNA fragmentation did not reach the statistical significance in rats given with nitrite nicardipine, diltiazem and verapamil. Further studies should be performed to investigate the formation of NOC in conditions simulating those occurring in the stomach of humans treated with a therapeutic dose, and to quantitate their genotoxic potency.
authors.affiliation: Department of Internal Medicine, Division of Clinical Pharmacology and Toxicology, University of Genoa, I-16132 Genoa, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Martelli
authors.forename: Luigi
authors.initials: L
authors.lastname: Robbiano
authors.forename: Sarah
authors.initials: S
authors.lastname: Grossi
authors.forename: Francesca
authors.initials: F
authors.lastname: Mattioli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Brambilla
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D020552:Comet Assay; D053938:DNA Fragmentation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D015394:Molecular Structure; D009603:Nitroso Compounds / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012977:Sodium Nitrite / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity; D013997:Time Factors
chemical_list: D002121:Calcium Channel Blockers; D009603:Nitroso Compounds; D012977:Sodium Nitrite