Collect. Czech. Chem. Commun. 2000, 65, 1374-1386

Biotransformation of Benfluron by Rat Hepatic Cytochrome P450. Identification of Individual CYP-Enzymes Involved in Biotransformation of Benfluron, Prospective Antineoplastic Based on Benzo[c]fluorene

Kamil Hrubý, Eva Anzenbacherová, Pavel Anzenbacher* and Milan Nobilis

Institute of Experimental Biopharmaceutics, Joint Research Center of PRO.MED.CS Praha a.s. and Academy of Sciences of the Czech Republic, Heyrovského 1207, 500 02 Hradec Králové 2, Czech Republic


Benfluron, 5-[2-(dimethylamino)ethoxy]-7H-benzo[c]fluoren-7-one hydrochloride, a prospective antineoplastic agent, is metabolised by cytochromes P450 to N-demethyl and 9-hydroxy derivatives. To prove the participation of individual cytochrome P450 isoforms in formation of these metabolites, selective induction of cytochromes P450, inhibition of benfluron biotransformation using inhibitors specific for individual cytochromes P450, and inhibition by benfluron of "marker" enzyme activities characteristic of certain cytochromes P450 were used. N-Demethylbenfluron appears to be formed mainly by the cytochromes P450 of the 3A, 2B and 2C subfamilies with possible participation of the isoform 2E1; 9-hydroxybenfluron is formed with participation of cytochromes P450 belonging to 1A, and most probably to 3A and 2E1 enzymes. The fact that benfluron is in this respect a relatively promiscuous substrate may be an advantage because its metabolism should not be influenced by the absence or low activity of some cytochrome P450 isoforms and by possible drug interactions.

Keywords: Cytochrome P450; Benzo[c]fluorenes; Biotransformations; Microsomes; Antitumor activity; Metabolism.

References: 36 live references.