This review summarises current knowledge about the genotoxic and genoprotective effects of 1,4-dihydropyridines (DHP) with the main focus on the water-soluble 1,4-DHPs. Most of these water-soluble compounds manifest very low calcium channel blocking activity, which is considered "unusual" for 1,4-DHPs. Glutapyrone, diludine, and AV-153 decrease spontaneous mutagenesis and frequency of mutations induced by chemical mutagens. AV-153, glutapyrone, and carbatones protect DNA against the damage produced by hydrogen peroxide, radiation, and peroxynitrite. The ability of these molecules to bind to the DNA may not be the only mechanism of DNA protection, as other mechanisms such as radical scavenging or binding to other genotoxic compounds may take place and enhance DNA repair. These uncertainties and reports of high 1,4-DHP concentrations damaging the DNA call for further in vitro and in vivo preclinical research, pharmacokinetic in particular, as it can help pinpoint the exact mechanism(s) of the genotoxic and/or genoprotective action of 1,4-DHPs.
Ovaj pregledni rad donosi sažetak onoga što smo dosad naučili o genotoksičnom i genoprotektivnom djelovanju 1,4-dihidropiridina (DHP), s posebnom pažnjom na 1,4-DHP-ove topljive u vodi. Većina tih u vodi topljivih spojeva slabo aktivira blokiranje kalcijevih kanala, što se smatra “neuobičajenim” za 1,4-DHP-ove. Glutapiron, diludin i AV-153 ublažavaju spontanu mutagenezu i učestalost mutacija prouzročene kemijskim mutagenima. AV-153, glutapiron i karbatoni štite DNA od oštećenja prouzročenih vodikovim peroksidom, zračenjem i peroksinitritom. Sposobnost tih molekula da se vežu za DNA vjerojatno nije jedini mehanizam njegove zaštite, budući da su mogući i drugi mehanizmi, poput uklanjanja radikala ili vezanja za druge genotoksične spojeve koji pospješuju popravak DNA. Zbog tih nepoznanica i izvještaja da visoke koncentracije 1,4-DHP-ova oštećuju DNA, potrebno je napraviti daljnja neklinička istraživanja in vitro i in vivo, napose ona farmakokinetička, budući da mogu pomoći razaznati točne mehanizme genotoksičnoga i/ili genoprotektivnoga djelovanja derivata 1,4-dihidropiridina.
Keywords: 1,4-DHP; AV-153; DNA binding; carbatones; diludin; diludine; glutapiron; glutapyrone; karbatoni; vezanje za DNA.
© 2023 Elina Leonova et al., published by Sciendo.