Induction of rat hepatic cytochrome P-450 I proteins by the antimutagen anthraflavic acid.
Administration of the antimutagen anthraflavic acid to rats gave rise to significant increases in the hepatic microsomal O-deethylations of ethoxyresorufin and ethoxycoumarin, but not in the O-dealkylation of pentoxyresorufin nor in cytosolic glutathione S-transferase activity. Immunoblot studies of solubilized microsomes from anthraflavic acid-treated rats revealed that anthraflavic acid induced the apoproteins P-450 I A1 and A2 but not P-450 B1 and B2. Pretreatment with anthraflavic acid resulted in a marked increase in the in vitro bioactivation of 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole and 2-amino-3,2-amino-3-methylimidazomethylimidazo[4,5-f]-quinoline (IQ) to mutagenic intermediate(s); IQ is a carcinogen against which anthraflavic acid has displayed strong antimutagenic effect in the Ames test when incorporated into the metabolic activation system. The increase in mutagenicity of IQ was the result of enhancement of both the microsomal and cytosolic activation steps. It is concluded that anthraflavic acid is a specific inducer of P-450 I proteins in the rat and this compound is not only unlikely to exhibit any anticarcinogenic effect in vivo but may act as a co-carcinogen.
Ayrton
A D
AD
Department of Biochemistry, University of Surrey, Guildford, England.
Ioannides
C
C
Walker
R
R
D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D008099:Liver / Q000201:enzymology; D008297:Male; D011804:Quinolines / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D000880:Anthraquinones; D011804:Quinolines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D003577:Cytochrome P-450 Enzyme System; C034889:2,6-dihydroxyanthraquinone