Mechanism of the in vitro antimutagenic action of retinol.
The antimutagenic action of retinoids against three amino-imidazoazaarene pre-carcinogens, i.e. 2-amino-3-methylimidazo(4,5-f)quinoline (IQ), 2-amino-3,4-dimethylimidazo(4,5-f)quinoline (MeIQ) and 2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline (MeIQx), was investigated using the Ames test and hepatic activation systems derived from rats pretreated with Aroclor 1254. Both retinol and retinal, when incorporated into the S9 activation system, gave rise to a concentration-dependent decrease in the mutagenicity of all three mutagens, retinol being generally the more effective. Retinol suppressed the mutagenic activity of IQ even when isolated microsomes were used as activation systems. Moreover, retinol gave rise to a concentration-dependent inhibition of the microsomal dealkylations of pentoxy- and benzyloxy- and, especially, ethoxy-resorufin, but had no effect on the NADPH-dependent reduction of cytochrome c. Exposure of the bacteria to retinol with subsequent removal of the vitamin did not influence the mutagenicity of IQ. It is concluded that retinoids suppress the mutagenicity of aminoimidazoazaarenes and this is achieved through inhibition of their cytochrome P450-dependent metabolic activation. Retinol is a non-selective in vitro inhibitor of the hepatic cytochrome P450-dependent mixed function oxidase system as predicted by a computer graphic analysis of its molecular shape.
Ioannides
C
C
Department of Biochemistry, University of Surrey, Guildford, UK.
Ayrton
A D
AD
Keele
A
A
Lewis
D F
DF
Flatt
P R
PR
Walker
R
R
D000818:Animals; D001711:Biotransformation; D003198:Computer Simulation; D066298:In Vitro Techniques; D008297:Male; D008954:Models, Biological; D009152:Mutagenicity Tests; D009251:NADPH-Ferrihemoprotein Reductase; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D011804:Quinolines / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013367:Submitochondrial Particles / Q000187:drug effects* / Q000378:metabolism; D014801:Vitamin A / Q000494:pharmacology*
D011804:Quinolines; D011810:Quinoxalines; D014801:Vitamin A; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; D010088:Oxidoreductases; D009251:NADPH-Ferrihemoprotein Reductase; C036989:2-amino-3,4-dimethylimidazo(4,5-f)quinoline