Inhibition of retinoic acid metabolising enzymes by 2-(4-aminophenylmethyl)-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one and related compounds.
In a search for inhibitors of all-trans retinoic acid (RA)-metabolising enzymes as potential agents for the treatment of skin conditions and cancer we have examined 2-(4-aminophenylmethyl)-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one (5). Compound (5) is a moderate inhibitor of RA-metabolising enzymes in mammalian cadaverous tissue microsomes and homogenates as well as RA-induced enzymes in cultured human genital fibroblasts and HaCat cells. Overall (5) was more potent than or equipotent with ketoconazole, a standard inhibitor, in the cadaverous systems but less active towards the RA-induced cell culture systems. Examination of the data suggests that RA-induction generates metabolising enzymes not present in the cadaverous systems, which are more susceptible to inhibition by ketoconazole than (5).
Kirby
Andrew J
AJ
Welsh School of Pharmacy, Cardiff University, Cathays Park, Cardiff CF10 3XF, UK.
Le Lain
Regis
R
Maharlouie
Farshid
F
Mason
Peter
P
Nicholls
Paul J
PJ
Smith
H John
HJ
Simons
Claire
C
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014212:Tretinoin / Q000378:metabolism*
C477687:2-(4-aminophenylmethyl)-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D014212:Tretinoin