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).
Welsh School of Pharmacy, Cardiff University, Cathays Park, Cardiff CF10 3XF, UK.
Andrew J
AJ
Kirby
Regis
R
Le Lain
Farshid
F
Maharlouie
Peter
P
Mason
Paul J
PJ
Nicholls
H John
HJ
Smith
Claire
C
Simons
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