title: Chemical structure and genotoxic activity of the hepatocarcinogenic beta-blocker DL-ZAMI 1305.
abstract: A single administration of the sex-dependent hepatocarcinogenic beta-blocker DL-1-(2-nitro-3-methyl-phenoxy)3-tert-butylamino-propan-2-ol (DL-ZAMI 1305) induces liver DNA damage, as evaluated by alkaline sucrose gradient analysis, in female but not in male Fisher 344 rats. The shift of the methyl-group from the 3-position of the aromatic ring of DL-ZAMI 1305 to the 4- and 5-position causes the progressive decrease of the genotoxic activity of the molecule. No effect on the DNA-damaging capacity of DL-ZAMI 1305 is instead observed when the NO2 group of the aromatic ring is reduced to an NH2 group. Bis-demethylation of the side chain of DL-ZAMI 1305, or its modification to an alpha-hydroxicarboxylic acid or glycol, increases the DNA-damaging capacity of the molecule, which becomes genotoxic also for the liver of the male rat. Thus, modifications of the chemical structure of the aromatic ring or of the side chain of DL-ZAMI 1305 affect the genotoxic activity of the molecule both in male and female rat liver. The modifications of the side chain of DL-ZAMI 1305 investigated in the present work are likely to occur in vivo as a consequence of the hepatic metabolism of the molecule. Sex-dependent differences in the activity of the liver drug-metabolizing system might explain the different genotoxic and oncogenic activity of DL-ZAMI 1305 in the two sexes.
authors.affiliation: Department of Biomedical Sciences and Biotechnologies, School of Medicine, University of Brescia, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Presta
authors.forename: F
authors.initials: F
authors.lastname: Legati
authors.forename: R
authors.initials: R
authors.lastname: Chiesa
authors.forename: P
authors.initials: P
authors.lastname: Dell'Era
authors.forename: G
authors.initials: G
authors.lastname: Ragnotti
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000633:toxicity*; D000818:Animals; D004249:DNA Damage; D005260:Female; D008099:Liver / Q000187:drug effects*; D008297:Male; D011412:Propanolamines / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D012737:Sex Factors; D013329:Structure-Activity Relationship
chemical_list: D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; C028475:ZAMI 1305