title: Identification of chalcones as in vivo liver monofunctional phase II enzymes inducers.
abstract: Cancer preventive agents (CPA) are drugs able to suppress the carcinogen metabolic activation or block the formation of ultimate carcinogens. CPA could act through various molecular mechanisms, for example by interfering with the action of procarcinogen. This could be attained by increasing the phase II enzymes levels of quinone reductase (QR) and glutathione S-transferase (GST). New flavonoids, especially chalcones, have been identified as in vivo monofunctional phase II enzymes inducers. Oral administration of chalcone, 4, and both p-methoxy-substituted chalcones, 6 and 14, increased hepatic QR activity with concomitant decrease in CYP1A1 activity, a member of the most important group of phase I enzymes cytochrome P450. Among them, 4 also increased GST activity. While p-bromo-substituted chalcone 8 was the best inducer of QR it decreased hepatic GST expression and cytochrome P450, being the most effective decreasing cytochrome P450-expression. Thienyl-chalcone 20 being the bioisostere of chalcone 4 did not display the same in vivo profile in the phase I level modification. As chalcone 4 its bioisostere, chalcone 20, displayed low DNA strand breakage and absence of mutagenicity. Also, in our preliminary in vivo tumourigenesis/chemopreventive and acute-toxicity studies, chalcones 4, 6 and 8 showed the best behaviours as CPA justifying additional studies that are ongoing.
authors.affiliation: Laboratorio de Química Orgánica, Facultad de Ciencias-Facultad de Química, Iguá 4225, Facultad de Ciencias, 11400 Montevideo, Uruguay.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Cabrera
authors.forename: María Laura
authors.initials: ML
authors.lastname: Lavaggi
authors.forename: Fiorela
authors.initials: F
authors.lastname: Croce
authors.forename: Laura
authors.initials: L
authors.lastname: Celano
authors.forename: Leonor
authors.initials: L
authors.lastname: Thomson
authors.forename: Marcelo
authors.initials: M
authors.lastname: Fernández
authors.forename: Cristina
authors.initials: C
authors.lastname: Pintos
authors.forename: Stella
authors.initials: S
authors.lastname: Raymondo
authors.forename: Mariela
authors.initials: M
authors.lastname: Bollati
authors.forename: Antonio
authors.initials: A
authors.lastname: Monge
authors.forename: Adela
authors.initials: A
authors.lastname: López de Ceráin
authors.forename: Oscar E
authors.initials: OE
authors.lastname: Piro
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
authors.forename: Mercedes
authors.initials: M
authors.lastname: González
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047188:Chalcones / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D020552:Comet Assay; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008113:Liver Neoplasms / Q000201:enzymology / Q000517:prevention & control*; D008958:Models, Molecular; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
chemical_list: D016588:Anticarcinogenic Agents; D047188:Chalcones; D019363:Cytochrome P-450 CYP1A1; D016660:NAD(P)H Dehydrogenase (Quinone)