CYP3A4-dependent cellular response does not relate to CYP3A4-catalysed metabolites of C-1748 and C-1305 acridine antitumor agents in HepG2 cells
PBN-AR
Instytucja
Wydział Chemiczny (Politechnika Gdańska)
Informacje podstawowe
Główny język publikacji
ENG
Czasopismo
CELL BIOLOGY INTERNATIONAL
ISSN
1065-6995
EISSN
Wydawca
DOI
URL
Rok publikacji
2014
Numer zeszytu
11
Strony od-do
1291-1303
Numer tomu
38
Link do pełnego tekstu
Identyfikator DOI
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Słowa kluczowe
ANTITUMOR ACRIDINES
APOPTOSIS
CELLULAR RESPONSE
CYP3A4 OVEREXPRESSION
DRUG METABOLISM
Streszczenia
Język
Treść
High CYP3A4 expression sensitizes tumor cells to certain antitumor agents while for others it can lower their therapeutic ef fi cacy. We have elucidated the in fl uence of CYP3A4 overexpression on the cellular response induced by antitumor acridine derivatives, C-1305 and C-1748, in two hepatocellular carcinoma (HepG2) cell lines, Hep3A4 stably transfected with CYP3A4 isoenzyme, and HepC34 expressing empty vector. The compounds were selected considering their different chemical structures and different metabolic pathways seen earlier in human and rat liver microsomes C-1748 was transformed to several metabolites at a higher rate in Hep3A4 than in HepC34 cells. In contrast, C-1305 metabolism in Hep3A4 cells was unchanged compared to HepC34 cells, with each cell line producing a single metabolite of comparable concentration. C-1748 resulted in a progressive appearance of sub-G1 population to its high level in both cell lines. In turn, the sub-G1 fraction was dominated in CYP3A4-overexpressing cells following C-1305 exposure. Both compounds induced necrosis and to a lesser extent apoptosis, which were more pronounced in Hep3A4 than in wild-type cells. In conclusion, CYP3A4-overexpressing cells produce higher levels of C-1748 metabolites, but they do not affect the cellular responses to the drug. Conversely, cellular response was modulated following C-1305 treatment in CYP3A4-overexpressing cells, although metabolism of this drug was unaltered.
Inne
System-identifier
129899
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