Optical isomers of the hepatocarcinogenic beta-blocker ZAMI 1305: influence on nucleic acids synthesis and DNA integrity.
The influence on nucleic acids synthesis and DNA integrity of the D-isomer and of the DL-racemic form of the oncogenic beta-blocker 1-(2-nitro-3-methyl-phenoxy)-3-tert-butylamino-propan-2-ol (ZAMI 1305) and of the non-oncogenic beta-blocker propranolol was tested in vitro and in vivo. Both D- and DL-ZAMI 1305, when added in vitro to nuclei isolated from rat liver, cause inhibition of DNA and RNA synthesis and DNA fragmentation, as evaluated by alkaline sucrose gradient analysis, in a similar dose-dependent fashion. D- and DL-ZAMI 1305 also inhibit to a similar extent the activity of DNA polymerase alpha and beta from regenerating rat liver. When administered in vivo to female rats both D and DL-ZAMI 1305 cause a dose-dependent fragmentation of liver DNA. The D-isomer and DL-racemic form of the non-oncogenic beta-blocker propranolol inhibit DNA and RNA synthesis and cause DNA fragmentation when added in vitro to isolated liver nuclei, being instead without effect when administered in vivo.
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D004256:DNA Polymerase I / Q000378:metabolism; D004257:DNA Polymerase II / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects*; D005260:Female; D006168:Guinea Pigs; D007536:Isomerism; D008099:Liver / Q000378:metabolism; D008297:Male; D009904:Optical Rotation; D011412:Propanolamines / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis*; D051381:Rats; D011919:Rats, Inbred Strains
D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D012313:RNA; C028475:ZAMI 1305; D011433:Propranolol; D004256:DNA Polymerase I; D004257:DNA Polymerase II