Identification of chalcones as in vivo liver monofunctional phase II enzymes inducers.
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.
Cabrera
Mauricio
M
Laboratorio de Química Orgánica, Facultad de Ciencias-Facultad de Química, Iguá 4225, Facultad de Ciencias, 11400 Montevideo, Uruguay.
Lavaggi
María Laura
ML
Croce
Fiorela
F
Celano
Laura
L
Thomson
Leonor
L
Fernández
Marcelo
M
Pintos
Cristina
C
Raymondo
Stella
S
Bollati
Mariela
M
Monge
Antonio
A
López de Ceráin
Adela
A
Piro
Oscar E
OE
Cerecetto
Hugo
H
González
Mercedes
M
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
D016588:Anticarcinogenic Agents; D047188:Chalcones; D019363:Cytochrome P-450 CYP1A1; D016660:NAD(P)H Dehydrogenase (Quinone)